Introduction: Current UK guidelines recommend measurement of symphyseal fundal height and measurement of maternal blood pressure and urinalysis, with the aim of detecting women at increased risk of fetal growth restriction (FGR) and preeclampsia. Between 2008 and 2013 we conducted a prospective cohort study recruiting 4,512 nulliparous women at the Rosie Hospital, Cambridge, where we performed serial ultrasonic imaging and serial blood sampling and generated a novel screening test for preeclampsia and FGR. The method involved measuring the ratio of two placental biomarkers (soluble fms-like tyrosine kinase receptor-1 [sFLT1] and placenta growth factor [PlGF]) at ~36 weeks of gestational age (wkGA) and combining the result with maternal characteristics and ultrasonic imaging. Women who screened positive had a ~50% risk of a composite outcome, consisting of preeclampsia and/or delivery of a baby with a birth weight <3rd percentile for sex and gestational age and/or perinatal morbidity or death. It is plausible that screening and intervention using this method might improve pregnancy outcome. Methods and analysis: Nulliparous women with an apparently normal singleton pregnancy will be recruited at their dating ultrasound scan. Blood will be obtained at this visit, at their anomaly scan (20wkGA), and at two research appointments (28wkGA and 36wkGA) when research ultrasound scans will be performed. Blood for DNA will be obtained from the father of the baby where possible and the placenta will be sampled following birth. At 36wkGA, women will be consented for participation in the randomised controlled trial (RCT) element of the study and their risk of term preeclampsia and FGR will be assessed using the novel approach. Women who screen high-risk will then be randomly allocated to either having the result revealed or masked. Women randomised to having the result revealed will be offered early delivery and/or enhanced monitoring. Where the result is masked, there will be no communication between the research team and the participant, and she will continue to receive routine care at the Rosie Hospital. The primary outcome is a composite of preeclampsia, FGR and perinatal morbidity and mortality. The study will also generate data and biological samples to support future research in novel screening methods and disease mechanisms. Ethics and dissemination: The study received ethical approval from the East of England Research Ethics Committee. All women provide written informed consent to participate in the cohort. Women provide a second written informed consent to participate in the RCT. The study results will be disseminated by presentation at international conferences and publication in peer reviewed journals. Trial registration 07/10/2019: ISRCTN12181427 (https://doi.org/10.1186/ISRCTN12181427)

GS and DSC-J have received funding from Roche Diagnostics Ltd to support the study. This consisted of 436,577 GBP of payment in kind (loan of machine, consumables, servicing and training) and funds (100,000 GBP) to support research expenses (equipment and consumables). GS department received payment from Roche Diagnostics Ltd for a talk given by GS on the use of the sFLT1:PlGF ratio to predict fetal growth restriction in 2018. Roche Diagnostics Ltd also provided consumables and equipment to the value of 596,142 GBP in 2014 to perform the analysis of sFLT1 and PlGF in the original POP study samples. Outside the scope of this work (last three years): GS and DSC-J have received research support from Illumina and Pfizer (fetal growth restriction and preeclampsia, preterm birth and infection). GS is/has been a paid consultant to GSK (preterm birth), Natera (biomarker discovery), Medicines360 (screening in pregnancy), and is/has been a member of Data Monitoring Committees trials of vaccination in pregnancy (GSK and Moderna) and a novel therapeutic for hyperemesis gravidarum (NGM Biopharmaceuticals). DSC-J is/has been a paid consultant to Medicines360 (screening in pregnancy) and GondolaBio (pregnancy related diagnostics and therapeutics). GS, DSC-J and US are named inventors in a series of patents for the prediction of fetal growth restriction, preeclampsia and gestational diabetes mellitus in pregnancy, filed by Cambridge Enterprise and licensed to Medicines360.

ISRCTN12181427

The primary source of funding for the present study is the Wellcome Trust (3,184,828 GBP). The study receives additional funding from Roche Diagnostics Ltd, who provide the resources required to perform the quantitation of sFlt1 and PlGF plus 100,000 GBP. Extracts from the contracts with Roche Diagnostics Ltd are provided as an additional file. The study also receives support from the NIHR Clinical Research Network, who provide salary support for research staff who recruit participants; the NIHR Cambridge Clinical Research Facility, which provide the rooms where the study visits take place and who provide supporting staff (nursing, administrative, phlebotomy and sample processing), and the Antenatal, Maternal and Child Health theme of the NIHR Cambridge Biomedical Research Centre, which funds core posts in the Department of Obstetrics and Gynaecology, University of Cambridge (UK), which support the study. IW was supported by the Medical Research Council Programme MC_UU_00004/07. None of the funders have contributed to or have authority over the design of the study, the collection, analysis, and interpretation of data or writing of manuscripts.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study has been approved by the East of England (Essex) Research Ethics Committee (19/EE/0331), the NHS Health Research Authority (IRAS271826) and the Cambridge University Hospital NHS Foundation Trust Research and Development Office (A095380).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Participant level data will not be publicly available but may be shared with appropriately qualified researchers through a Data Transfer Agreement, which would require an appropriately authorised signatory from the receiving institution.