Pregnancy outcome prediction study 2

Plain English Summary

Background and study aims
Screening for pregnancy complications around delivery has not changed very much over the last 30 years. Moreover, we know that the methods currently employed, such as measuring the size of the “bump” with a tape measure, do not perform well

The aims of this trial are:
1. To determine whether a new approach, using ultrasound and blood tests, is effective at picking up high risk pregnancies, and
2. Whether intervening in the pregnancy, based on the result, reduces the risk. Intervention will consist primarily of the offer of earlier delivery by induction of labour

Who can participate?
Women with a singleton pregnancy at the time of their dating ultrasound scan who have not had any previous births

What does the study involve?
We will obtain blood at around 12, 20, 28 and 36 weeks of gestation from the women and blood from the father of the baby (if present and consents) at one of these visits. We will also obtain samples at the time of birth, including placenta, membranes and blood from the umbilical cord. We will collect data from the participants through a questionnaire and by performing ultrasound scans at around 20, 28 and 36 weeks. We will link the research data to the woman's and baby's clinical records. The data and biological samples will provide a resource to develop and validate predictive tests for adverse pregnancy outcome. However, in addition to this, we will also perform a randomised controlled trial. Using data from the Pregnancy Outcome Prediction study, we have developed a test which identifies women at high risk of complications at around eight months of pregnancy (36 weeks). The blood sample, scan information and mother's characteristics will be used to identify women at high risk following the 36 week visit. These women will be randomised to have routine care (meaning that the high risk status will not be revealed) or to have the result revealed with the offer of intervention, principally, early delivery of the baby by induction of labour. The primary outcome of the trial is a composite of either preeclampsia (a pregnancy-specific complication resulting in high blood pressure and other problems) in the mother or growth restriction of the baby

What are the possible benefits and risks of participating?
Participating involves some additional blood tests and these can cause mild discomfort and bruising. One benefit of participating is that we will reveal some scan information when it shows that there is a major problem. For example all women in the study will be told if there baby is in a breech presentation at 36 weeks. This allows time to try and turn the baby or to plan a caesarean delivery. In relation to the women who screen high risk, those who are randomised to having the result revealed and receiving intervention may either experience risks or benefits. We do not know the balance and this is the reason for doing the research. Women who screen high risk where the result is incorrect (i.e. they would have had a normal outcome if left alone) may experience an unnecessary intervention, specifically early induction of labour. However, women who screen high risk where the result is correct may benefit by avoiding complications of pregnancy through earlier delivery, before the complication can happen

Where is the study run from?
The Rosie Hospital, UK

When is the study starting and how long is it expected to run for?
January 2020 to June 2026

Who is funding the study?
Wellcome Trust, UK

Who is the main contact?
Prof. Gordon Smith
gcss2@cam.ac.uk

Study website

https://www.obgyn.cam.ac.uk/research/pops-2/pops2/

Type

Scientific

Contact name

Prof Gordon Smith

ORCID ID

http://orcid.org/0000-0003-2124-0997

Contact details

Department of Obstetrics and Gynaecology
Cambridge University
Box 223 The Rosie Hospital
Robinson Way
Cambridge
CB2 0SW
United Kingdom
+44 (0) 1223 336871
gcss2@cam.ac.uk

EudraCT/CTIS number

Nil known

IRAS number

271826

ClinicalTrials.gov number

Nil known

Protocol/serial number

215524/Z/19/Z, IRAS 271826

Scientific title

The evaluation and development of novel diagnostic methods to understand and prevent placentally-related complications of human pregnancy

Acronym

POPS2

Study hypothesis

1. Screening nulliparous pregnant women using measurement of sFLT1/PlGF ratio at ~36 weeks of gestational age (wkGA) identifies women at increased risk of placentally-related complications at term
2. Revealing the result of screening using the sFLT1/PlGF ratio at ~36wkGA reduces the risk of maternal and perinatal morbidity and mortality
3. Measurement of other biomarkers in maternal blood may enhance risk prediction of placentally-related complications of pregnancy

Ethics approval(s)

Approved 23/12/2019, East of England - Essex Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 1048106; NRESCommittee.EastofEngland-Essex@nhs.net), ref: 19/EE/0331

Study design

Prospective cohort study with nested randomised controlled trial of screening and intervention

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Screening

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Pre-eclampsia and fetal growth restriction

Intervention

Women will be recruited at their dating ultrasound scan, typically performed ~12wkGA. 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. At the 36wkGA visit, women will be consented for participation in the RCT element of the study. For those who consent, their risk of term preeclampsia and/or fetal growth restriction will be calculated using a rule derived from the original POP study and based around the sFLT1/PLGF ratio. Women who screen high risk will then be randomly allocated to either having the result revealed or masked. Where the result is masked, there will be no communication of the risk score with the participant and she will continue to receive the standard of care at the Rosie Hospital. Women who screen high risk and are randomised to intervention will be reviewed and their results discussed. They will be offered early delivery, typically induction of labour between 37wkGA and 39wkGA where the clinical management of induction will follow the standard hospital protocols for high risk women.

Both arms will be followed up until the mother is discharged following the hospital admission when she delivered. Randomisation will be with minimisation based on the four elements of the screening assessment.

Randomisation:
The randomisation list will be computer-generated by an independent statistician and provided for incorporation into the study database by the data manager

Intervention type

Mixed

Primary outcome measure

The primary outcome is a composite, namely, one or more of the following:
1. Diagnosis of preeclampsia (using the ACOG 2013 definition),
2. Perinatal death or perinatal morbidity, or
3. Delivery of an infant with a birth weight <3rd percentile for sex and gestational age

Perinatal death will be defined as stillbirth or neonatal death. Perinatal morbidity is defined as ≥1 of the following: a 5 minute Apgar score <7, delivery with metabolic acidosis (defined as a umbilical cord artery or vein pH <7.1 and a base deficit of >10mmol/L) or admission to the neonatal unit (defined as admission <48 hours after birth and discharge ≥48 hours after admission). We will also study a subgroup of the primary outcome, namely, composite severe adverse outcome. This will be defined as one or more of the following: (i) preeclampsia with severe features (ACOG 2013 definition) (ii) perinatal death or severe perinatal morbidity. Severe perinatal morbidity will be defined as livebirth associated with hypoxic ischaemic encephalopathy (any grade), use of inotropes, mechanical ventilation, or severe metabolic acidosis (defined as a umbilical cord artery or vein pH <7.0 and a base deficit of >12mmol/L.

Secondary outcome measures

Secondary outcomes will include each of the individual elements of the maternal and perinatal composite described above. The following additional secondary outcomes will be studied:
1. Maternal:
1.1 Maternal death
1.2 Maternal stroke
1.3 Maternal admission to any medical unit (e.g. intensive care unit, stroke unit, coronary care unit, neurosciences critical care unit)
1.4 Placental abruption
1.5 Cord prolapse
1.6 Caesarean section
1.7 Epidural anaesthesia
1.8 Instrumental vaginal delivery
1.9 General anaesthesia
1.10 Post-partum haemorrhage (any >500ml)
1.11 Post-partum haemorrhage requiring blood transfusion
1.12 Infection (pyrexia >38°C and treated with a course of antibiotics)
Maternal death, stroke, admission to a medical unit, hemorrhage and infection will include all episodes occurring prior to discharge home following the delivery.

2. Perinatal:
2.1 Apgar at 1 minute
2.2 Apgar at 5 minutes
2.3 Apgar at 10 minutes
2.4 Umbilical arterial pH and base deficit
2.5 Umbilical vein pH and base deficit
2.6 Any/duration of admission to Special Care
2.7 Any/duration of admission to Neonatal Intensive Care
2.8 Fracture (any)
2.9 Seizures (any)
2.10 Prolonged hypotonia (>2h)
2.11 Abnormal level of consciousness (hyperalert, drowsy, lethargic, stupor, decreased response to pain, coma)
2.12 Tube feeding (any duration)
2.13 Head cooling
2.14 Phototherapy
2.15 Severe hypoglycemia (defined as requiring parenteral treatment or drug therapy)

Overall study start date

10/05/2018

Overall study end date

30/06/2026

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Nulliparous (no previous births >23wkGA)
2. Single viable fetus at the dating ultrasound scan with an ultrasonic estimated gestational age <18wkGA

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Sex

Female

Target number of participants

12,150

Participant exclusion criteria

Does not meet inclusion criteria

Recruitment start date

01/01/2020

Recruitment end date

30/06/2025

Countries of recruitment

England, United Kingdom

Study participating centre

The Rosie Hospital
Robinson Way
Cambridge
CB2 0SW
United Kingdom

Organisation

Cambridge University Hospitals NHS Foundation Trust

Sponsor details

R&D Department
Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
England
United Kingdom
+44 (0) 1223 348490
research@addenbrookes.nhs.uk

Sponsor type

Hospital/treatment centre

Website

https://www.cuh.nhs.uk/research-and-development

ROR

https://ror.org/04v54gj93

Organisation

Cambridge University

Sponsor details

Clinical School
Cambridge
CB2 0SP
England
United Kingdom
+44 (0) 1223 336871
paoandghod@medschl.cam.ac.uk

Sponsor type

University/education

Website

https://www.medschl.cam.ac.uk/

Funder type

Charity

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

International organizations

Location

United Kingdom

Publication and dissemination plan

The primary publication arising from the study will report the primary and secondary outcomes of the trial comparing three groups:
1. Women who screened low risk
2. Women who screened high risk but were randomized to routine care, and
3. Women who screened high risk and were randomized to having the result revealed with the offer of intervention
Further publications will arise from the analysis of the study cohort

Intention to publish date

01/09/2026

Individual participant data (IPD) sharing plan

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request

IPD sharing plan summary

Available on request

Study outputs