Clinical trial NCT03674606: Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
Official title: An Open-label Randomized-Controlled Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pre-Eclampsia
Placenta Diseases
Eclampsia Preeclampsia
Fetal Growth Retardation
Foetal Growth Restriction
Keywords: 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
Lead sponsor: University College Dublin
Sponsor class: OTHER
Collaborators: name: Perinatal Ireland
name: National Maternity Hospital, Ireland
name: Royal College of Surgeons, Ireland
First posted: 2018-09-17
Enrollment: 546
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Three-armed parallel, multi-center, open-label randomised control trial
Primary purpose: PREVENTION

Brief summary: A study of aspirin use in pregnancy to prevent high blood pressure and growth restriction of the fetus

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The proportion of eligible women that agree to participate in the study
timeFrame: Throughout study completion, less than 40 weeks
measure: Adherence to aspirin if prescribed
timeFrame: 36 weeks
measure: The proportion of study subjects in whom it is possible to obtain first trimester trans-abdominal uterine artery Doppler examination
timeFrame: 36 weeks
measure: The proportion of study subjects with a completed screening test who are issued the screening result within one week of having the test performed
timeFrame: 1 week
measure: Attendance at study visits
timeFrame: 36 weeks
measure: Satisfactory collection of all endpoints and variables
timeFrame: 36 weeks
measure: Any specific study protocol violations
timeFrame: 36 weeks
Secondary outcomes:
measure: The rate of pre-eclampsia as defined by the International Society for the Study of Pre-eclampsia in Pregnancy.
timeFrame: Childbirth
measure: The rate of fetal growth restriction.
timeFrame: Childbirth
measure: Spontaneous or iatrogenic delivery.
timeFrame: Prior to 34 and 37 completed weeks of gestation
measure: Rate of admission to the neonatal intensive care unit.
timeFrame: Childbirth
measure: Patient acceptability: ease of swallowing medication proportioned between categories of a 5-point Likert scale from "strongly agree" to "strongly disagree"
timeFrame: 20--22 weeks
measure: Patient acceptability: reasons of failing compliance with study intervention regimen proportioned between answers to a 5-point multiple-choice question.
timeFrame: 20--22 weeks
measure: Patient acceptability: opinions on the screening test proportioned between categories of a 3-point rating scale ranging from "Useful" to "Inconvenient"
timeFrame: 20--22 weeks
measure: Patient acceptability: opinions for taking study intervention in the future proportioned between answers to a 3-point multiple-choice question.
timeFrame: 20--22 weeks
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: National Maternity Hospital
city: Dublin
country: Ireland
facility: Rotunda Hospital
Study officials:
References:
citation: Mone F, Mulcahy C, McParland P, Stanton A, Culliton M, Downey P, McCormack D, Tully E, Dicker P, Breathnach F, Malone FD, McAuliffe FM. An open-label randomized-controlled trial of low dose aspirin with an early screening test for pre-eclampsia and growth restriction (TEST): Trial protocol. Contemp Clin Trials. 2016 Jul;49:143-8. doi: 10.1016/j.cct.2016.07.003. Epub 2016 Jul 6.