Trial of Early Screening Test for Pre-eclampsia and Growth Restriction

Study Overview
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Brief Summary
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A study of aspirin use in pregnancy to prevent high blood pressure and growth restriction of the fetus

Detailed Description
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Ischemic placental disease (IPD) is an entity encompassing pre-eclampsia, fetal growth restriction (FGR) and placental abruption and has a combined incidence in pregnancy of 10-15%. Pre-eclampsia is a serious systemic condition affecting 3-5% of pregnancies and is responsible for > 50,000 of maternal deaths annually worldwide. The International Society for the Study of Hypertension in Pregnancy defines pre-eclampsia as gestational hypertension with proteinuria of 300 mg or more in 24 h. The use of low dose aspirin (LDA) prior to 16-weeks' gestation can prevent the pathological process causing placental disease by altering the balance of prostacyclin and thromboxane; hence preventing spiral artery thrombosis and widespread endothelial dysfunction. There is extensive evidence, demonstrating the efficacy and safety of LDA for prevention of placental disease in high-risk pregnancies where there are clearly identifiable risk factors. However, there is a paucity of research into its efficacy in low-risk women. Administration of aspirin in pregnancy is associated with absolute risk reductions of 2% to 5% for pre-eclampsia, 1% to 5% for FGR 2% to 4% for preterm delivery with no associated increase in perinatal or maternal morbidity. Several screening tests have been devised to detect the risk of pre-eclampsia and FGR from the first trimester. One of the most notable is that of The Fetal Medicine Foundation (FMF), UK that have devised an algorithm encompassing uterine artery Doppler pulsatility indices, mean arterial pressure (MAP), the placental biomarkers PAPP-A and PLGF in addition to maternal characteristics, which can detect 96% of cases of pre-eclampsia requiring delivery before 34 weeks and 54% of all cases of pre-eclampsia at a fixed false-positive rate of 10%. The FMF screening test is reserved as a research tool, pending validation within a low-risk population. Thus far it has been externally validated in other studies of unselected women with conflicting results as to sensitivity and specificity for placental disease prediction. Following validation of the FMF screening test in low-risk nulliparous women, which is currently the topic of on-going research, the FMF pre-eclampsia screening test may potentially come into clinical practice in the future. Current guidelines followed within the UK, set by The National Institute for Health and Clinical Excellence advocate screening through history taking and provision of LDA in the presence of one major risk factor or two moderate risk-factors. The American College of Obstetricians and Gynecologists have a similar stance and do not recommend screening to predict pre-eclampsia beyond obtaining an appropriate medical history to evaluate for risk factors. They recommend that any further screening tests beyond this should undergo a cost-effectiveness analysis before being used in routine practice. It has been postulated that it is more cost-effective to use prophylactic medication, notably aspirin for the prevention of placental disease rather than screening and treating an entire low-risk population. The reason for this is because aspirin is felt to be an effective, affordable and safe treatment in pregnancy. In light of such evidence, with an emerging novel screening test for pre-eclampsia and the efficacy of LDA for placental disease prevention it may be more clinically effective and affordable to prescribe LDA routinely to all women in their first pregnancy as opposed to being upon the basis of a screening test. To assess this hypothesis a preliminary pilot study is required to determine feasibility, acceptability and statistical power required for such a study. The study proposed is a three-armed parallel, multi-center, open-label randomized control trial (RCT) in low-risk women to determine; (i) the efficacy and (ii) the acceptability of women to take routine LDA, versus no LDA versus LDA on the basis of a pre-eclampsia screening test in their first pregnancy. It can be anticipated that the use of such a three-armed study will aid in determining if it is more acceptable to women and feasible to prescribe LDA routinely compared to not at all, or based on results of a screening test.

Official Title
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An Open-label Randomized-Controlled Trial of Early Screening Test for Pre-eclampsia and Growth Restriction

Conditions
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Pre-Eclampsia, Placenta Diseases, Eclampsia Preeclampsia, Fetal Growth Retardation, Foetal Growth Restriction

Intervention / Treatment
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* Drug: Low dose aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nulliparous women. Ability to speak and .read English Singleton pregnancy at <14 weeks. Willing to sign voluntarily a statement of informed consent to participate in the study. Exclusion Criteria: Presence of fetal anomaly at the time of the first trimester scan Women with known major risk factors for pre-eclampsia who should already be on Aspirin as per National Institute of Clinical Excellence (NICE) guidance; specifically chronic hypertension, underlying connective tissue, renal or vascular disorder, type 1 diabetes mellitus. Under 18 years of age. Currently enrolled in other clinical trials. Contraindications to Aspirin therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Three-armed parallel, multi-center, open-label randomised control trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Routine low-dose aspirin<br>Subjects shall receive standard antenatal care as well as taking oral low-dose aspirin from the eligibility visit until 36-week gestation once daily, as prescribed by the research clinician. Fetal Medicine Foundation screening test results from the recruitment visit shall not be disclosed to the participants in this arm. | Drug: Low dose aspirin<br>* One 75 mg aspirin dose taken daily<br>* Other names: 75 mg aspirin;|
| No Intervention: No aspirin<br>No low-dose aspirin will be prescribed. Fetal Medicine Foundation screening test results from the recruitment visit shall not be disclosed to the participants in this arm. | |
| Active Comparator: Test-indicated low-dose aspirin<br>The Fetal Medicine Foundation screening test will be used to determine whether a subject is at high risk of developing any pre-eclampsia until 42-week gestation. Participants with risk > 1:8 must start low-dose aspirin treatment immediately. Participants with a risk < 1:8 will be excluded. | Drug: Low dose aspirin<br>* One 75 mg aspirin dose taken daily<br>* Other names: 75 mg aspirin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of eligible women that agree to participate in the study | The proportion of eligible women that agree to participate in the study - this will be reflected as a proportion of the number of women approached at the screening stage (feasibility) | Throughout study completion, less than 40 weeks | 
| Adherence to aspirin if prescribed | Rate of adherence among study subjects prescribed aspirin. | 36 weeks | 
| The proportion of study subjects in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination | This outcome includes the subjectively recorded ease of acquisition (feasibility). | 36 weeks | 
| The proportion of study subjects with a completed screening test who are issued the screening result within one week of having the test performed | This includes the number of women within the screen and treatment group that went beyond 16-weeks before receiving the screening test result as beyond this time LDA may not be effective (feasibility). | 1 week | 
| Attendance at study visits | Rate of attendance of study visits by study subjects | 36 weeks | 
| Satisfactory collection of all endpoints and variables | Proportion of study subjects on which data for all other endpoints can be collected | 36 weeks | 
| Any specific study protocol violations | Proportion of study subjects for which protocol violations are recorded | 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of pre-eclampsia as defined by the International Society for the Study of Pre-eclampsia in Pregnancy. |  | Childbirth | 
| The rate of fetal growth restriction. |  | Childbirth | 
| Spontaneous or iatrogenic delivery. |  | Prior to 34 and 37 completed weeks of gestation | 
| Rate of admission to the neonatal intensive care unit. | rate of placental abruption, any reported death (stillbirth, neonatal or infant death) and small for gestational age infants. | Childbirth | 
| Patient acceptability: ease of swallowing medication proportioned between categories of a 5-point Likert scale from strongly agree to strongly disagree | Proportion of subjects who either 1) strongly agree, 2) agree, 3) neither agree/disagree, 4) disagree or 5) strongly disagree with the statement Aspirin was easy to swallow. | 20--22 weeks | 
| Patient acceptability: reasons of failing compliance with study intervention regimen proportioned between answers to a 5-point multiple-choice question. | Proportion of subjects who chose either Reservations of taking aspirin, Bleeding, It caused stomach upset, I forgot or Other as a reason for missing aspirin dose. | 20--22 weeks | 
| Patient acceptability: opinions on the screening test proportioned between categories of a 3-point rating scale ranging from Useful to Inconvenient | Proportion of subjects who chose either 1) Useful, 2) Neither useful/inconvenient or 3) Inconvenient to complete the statement With regards the screening test I found it | 20--22 weeks | 
| Patient acceptability: opinions for taking study intervention in the future proportioned between answers to a 3-point multiple-choice question. | Proportion of subjects who chose either Take aspirin routinely, Take aspirin only if I was at risk or Neither to complete the statement In a future pregnancy I would | 20--22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pre-eclampsia, Fetal Medicine Foundation, FMF screening, First trimester, Aspirin, Placental disease, nulliparous, LDA, low-dose aspirin, fetal growth restriction, trans-abdominal uterine artery doppler examination