The identification of novel biomarkers for the small for gestational age human fetus

Lead Research Organisation: University of Cambridge
Department Name: Research Services Division

Abstract

Babies who grow poorly in the womb (called small for gestational age [SGA]) are at increased risk of a number of adverse outcomes, including stillbirth. Screening pregnant women in an attempt to detect SGA babies has the potential to reduce the number of these adverse outcomes, in particular stillbirth, which accounts for the death of about 4000 babies per annum in the UK. Current practice in the UK in screening the general population for SGA babies is confined to measuring the woman?s bump (technically called ?symphysis-fundal height?) with a tape measure. However, this approach is known not to be particularly good at picking up small babies. The approach to SGA is very crude in comparison to the approach to screening for Down?s syndrome babies in pregnancy. Down?s syndrome screening utilises a combination of scan and blood markers and now detects 90% of cases with only a small proportion of women requiring further tests. There are also a number of scan and blood markers for SGA babies, but none of these is good enough on its own to predict them. We believe that it will be possible to identify novel markers which may be more effective than existing blood tests. In fact, relatively few studies have systematically looked for better markers and most of the existing blood tests which could help predict SGA were discovered by chance. We have access to scan information, blood samples and placental (afterbirth) samples from a large scale study of unselected women in their first pregnancy ( 2800 women and on target to recruit 5000). The overarching aim of the present application is to see if we can find better markers in the mother?s blood of poorly grown babies. Specifically, we plan to determine the key differences in the genes expressed in the placenta of SGA babies and matched controls. We then aim to see if the proteins encoded by these genes are found at different concentrations in the placenta and in the mother?s blood. Finally, we aim to determine whether information about the levels of these proteins improves the prediction of SGA babies. The end result will be a predictive tool (algorithm) to detect small babies. We could then design trials of the tool to see if it improved outcome. The ultimate aim is to make care of pregnant women more effective and to reduce the number of babies lost to stillbirth.

Technical Summary

Small for gestational age infants (SGA) are at increased risk of a number of adverse outcomes. Screening for SGA has the potential to reduce the number of adverse outcomes, in particular population rates of stillbirth, which account for the death of about 4000 babies per annum in the UK. The 2008 NICE Guideline on Antenatal Care identified improving detection of SGA infants as one of 5 major research priorities. The current exemplar of pregnancy screening is Down?s syndrome, which utilises a combination of ultrasonic and biochemical markers and now detects 90% of cases for a less than 5% false positive rate. We have previously reported associations between a range of ultrasonic and biochemical measurements and the risk of delivery of a SGA infant, but none of these has the discrimination to provide clinically useful prediction. We have hypothesised that this may be achieved by combined ultrasonic and biochemical assessment of the fetus and placenta. The current project will use the Pregnancy Outcome Prediction study, a prospective cohort study of unselected nulliparous women. The study combines serial ultrasonic fetal biometry and utero-placental Doppler and maternal blood sampling at 12, 20, 28 and 36 weeks; and systematic sampling of the placenta following delivery. The study has already recruited 2800 women, has placental samples stored from 1900 women and continues to recruit approximately 100 women per month. The design of the study allows optimal phenotyping of cases of SGA (using both Doppler and growth velocity) and comparison with controls matched in relation to key maternal and obstetric characteristics. Preliminary analysis of the ultrasonic data indicated that an algorithm based on scan data alone only picked up about half of SGA infants for a 10% screen positive rate. The aims of the present study are (1) to compare expression gene array of placental samples from infants with different phenotypes of SGA at term and to compare them with matched controls, (2) to validate variation in placental levels of candidate biomarkers using qRT-PCR, Western blot and immunohistochemistry in a separate series of cases and matched controls, (3) to use a case cohort approach to compare maternal serum levels of candidate biomarkers and assess their screening performance in combination with serial ultrasound. The ultimate aim is to generate an algorithm for the identification of pathologically SGA infants that might ultimately be tested in a randomised controlled trial of screening the general population.

Publications

10 25 50
 
Description Wrote chapter for the Chief Medical Officer's Annual Report 2014 on Antenatal Screening
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
URL https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/484383/cmo-report-2014.pdf
 
Description NIHR Research Capability Funding
Amount £20,916 (GBP)
Funding ID 3819151622 
Organisation Cambridge University Hospitals NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 08/2015 
End 03/2016
 
Description Prediction of Fetal Growth Restriction: Individual Participant Data (IPD) Meta-Analysis With Decision Curve AnalysisInternational Prediction of Complications in Pregnancy: Fetal Growth restriction (IPPIC-FGR)
Amount £264,304 (GBP)
Funding ID HTA/17/148/07 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 05/2019 
End 09/2020
 
Description Returning Carers Scheme 2014/15: third round
Amount £2,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 05/2015
 
Description The evaluation and development of novel diagnostic methods to understand and prevent placentally-related complications of human pregnancy
Amount £2,764,336 (GBP)
Funding ID 215524/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 07/2025
 
Title Placental DNA methylation data 
Description human placental DNA methylation and hydroxymethylation data and the identification of placental specific transcripts and promotor for the CSMD1 gene. Data available in the the EGA (https://www.ebi.ac.uk/ega/) EGAD00001003136 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact None to date as only recently published 
 
Title Placental RNASeq data 
Description RNASeq data from normal human pregnancy 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact None to date as only recently published. 
 
Description Clinical Research Agreement with Roche 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution We had conducted a prospective cohort study of unselected nulliparous women (the Pregnancy Outcome Prediction study). We collected ~16,000 serum and plasma samples from ~4,500 pregnant women, and have detailed clinical information on exposures and adverse outcomes. A team of technicians manage the biobank. This was funded by the NIHR Cambridge Comprehensive Biomedical Research Centre, and management of the biobank and sample analysis is support by an MRC project grant, G1100221 (The identification of novel biomarkers for the small for gestational age human fetus). The collaboration has allowed us to expand substantially the aims outlined in that grant to measure a series of placental biomarkers in pregnancies complicated by fetal growth restriction. With the collaboration, we are now able to measure placental biomarkers in the entire cohort, rather than perform a case control or case cohort study. We have completed approximately 80,000 ELISAs through the combined effort of the MRC Grant and the first outputs were published in early 2017.
Collaborator Contribution Roche provided a loan of a clinical grade immunoassay system (Cobas e411) and reagents to analyse 5 placental biomarkers (PAPP-A, AFP, hCG, sFlt-1 & PlGF) in all ~16,000 samples. They also provided training of our staff, and a maintenance contract plus technical support. The valuation of £596142.00 was costed by Roche.
Impact Prediction of preeclampsia using the sFLT-1:PIGF ratio: a prospective cohort study of unselected nulliparous women (http://doi:10.1016/j.preghy.2016.08.047) Screening for late fetal growth restriction using ultrasound and the sFlt-1:PlGF ratio Prediction of Preeclampsia Using the Soluble fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: A Prospective Cohort Study of Unselected Nulliparous Women
Start Year 2014
 
Description Sequencing Core 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Unique biological samples for sequence analysis
Collaborator Contribution Next generation sequencing
Impact Lots of new sequencing data, still being analysed
Start Year 2013
 
Title Randomised controlled trial of screening and intervention in unselected nulliparous women using sFLT1:PlGF ratio 
Description Measurement of sFLT1:PlGF in maternal serum has been shown to have predictive value for pre-eclampsia and fetal growth restriction in un-selected nulliparous women (see PubMed ID 30119716 and 28167687). These findings led to a successful application to the Wellcome Trust (£2.76 million) to fund a randomised controlled trial of screening and intervention using this test in this population. The details of the trial are provided in a public registry: ISRCTN12181427. The RCT commenced recruitment on 13/01/2020 and is expected to report ~2025. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
Impact None. 
 
Description 5th International FGM Conference, Toronto, Canada 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to be a panel member, title 'Screening for IUGR Panel Discussion and Q&A' 18 November 2016
Year(s) Of Engagement Activity 2016
URL http://www.fetalgrowth2016.ca/
 
Description 5th International FGM Conference, Toronto, Canada 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to take part in the panel discussion entitled 'Convergence on Current IUGR Guidelines Panel Discussion and Q&A' 18 November 2016
Year(s) Of Engagement Activity 2016
URL http://www.fetalgrowth2016.ca/
 
Description CTR 10th Anniversary Meeting, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor Gordon Smith invited to present at the CTR 10th Anniversary Meeting which took place 9-11 July 2017, Cambridge, UK. Title of talk "Placental biomarkers for adverse pregnancy outcome".
Year(s) Of Engagement Activity 2017
URL https://www.trophoblast.cam.ac.uk/
 
Description EAOGS Autumn meeting, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor Smith was personally invited to present as part of the EAOGS Autumn meeting 17 October in Cambridge. The title of his talk was 'The future of screening for fetal growth restriction'.
Year(s) Of Engagement Activity 2015
 
Description Edinburgh Obstetrical Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor Gordon Smith was invited by the Senior Secretary of the Edinburgh Obstetrical Society to speak at their monthly meeting which will take place 9 March 2016. The title of his talk will be 'Screening for adverse pregnancy outcomes'. All travel costs associated with this invitation will be covered.
Year(s) Of Engagement Activity 2016
 
Description Fetal Medicine Symposium, Wales 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited to speak at the symposium, title 'Beyond the measuring tape - screening for IUGR'
Year(s) Of Engagement Activity 2017
 
Description Glasgow Obstetrical & Gynaecological Society (GOGS), Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited to present at the GOGS regular evening seminar. Title 'Prevention of stillbirth' presented 15 February.
Year(s) Of Engagement Activity 2017
URL http://www.gogs.org.uk/meetings.htm
 
Description ISUOG - Ultrasound in preventing stillbirth 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Gordon Smith invited to run a workshop at the ISUOG conference held 20-24 October 2018 in Singapore.
Year(s) Of Engagement Activity 2018,2019
URL https://www.isuog.org/events/past-world-congresses.html
 
Description Lecture and visit to Illumina, Redwood City, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Invited to visit and present a lecture at Illumina. Research collaboration discussions also took place.
Year(s) Of Engagement Activity 2016
 
Description O&G Grand Round, School of Medicine, Yale University, Connecticut, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited to present at the Grand Round, Yale University 13 October 2016. All travel and related expenses covered by Yale University.
Year(s) Of Engagement Activity 2016
 
Description RCOG Annual Academic Award presentation, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Professor Gordon Smith invited to give a presentation as part of the award ceremony where he was presented with the RCOG Annual Academic Award. Title 'Screening for adverse pregnancy outcome: the future' given 2 March
Year(s) Of Engagement Activity 2017
 
Description Royal Maternity Hospital / Queens University Perinatal Annual Lecture, Belfast, Ireland 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor Smith was personally invited by the organisers of the Perinatal Annual Lecture at Royal Maternity Hospital / Queens University to be their speaker for 2015. The lecture is followed by a dinner. It took place 1 October in Belfast, Ireland. All associated travel costs were covered by the organisers. The title of the talk was 'Screening for fetal growth restriction'.
Year(s) Of Engagement Activity 2015
 
Description Scottish Government Stillbirth Conference, Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited to be a member of the panel 'Induction of Labour at 39 weeks, what harm can it do? Speaking 'for'.
Year(s) Of Engagement Activity 2017
URL http://www.sad.scot.nhs.uk/support-around-death-news/2017/january/edinburgh-international-conference...
 
Description Stillbirth update and risk factors Workshop, Melbourne, Australia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Professor Smith was invited to speak at the Stillbirth update and risk factors Workshop, which took place 28-29 November 2017, Melbourne, Australia. Title of talk "Screening and intervention to prevent stillbirth".
Year(s) Of Engagement Activity 2017