IMproved PRegnancy Outcome by Early Detection

Louise Kenny5,000 enrolled

Overview

The overall objective of the IMPROvED project is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for preeclampsia. This will involve a multicentre, phase IIa clinical predictive study to assess and refine novel and innovative prototype tests based on emerging metabolomic and proteomic technologies developed by SMEs (small to medium size enterprise) within the consortium. The study will i) recruit 5000 first-time pregnant women; ii) establish a high calibre biobank, augmented by accurate clinical metadata; iii) determine whether prototype predictive assays and algorithms translate to the clinical environment; iv) assess potential synergy of a combined metabolomic and proteomic approach and v) progress regulatory approval and development of the selected test into the clinical arena.

Sample size calculations have been considered extensively and given the complexity of the study; there is no single simple solution. For the purpose of sample size estimation in the overall study, we used a binary outcome and associated measures of sensitivity and likelihood ratio as determinants of the value of these tests. Although the predictive algorithms will produce a continuous risk score, the use of a categorical outcome fits with the final binary decision process (to treat or not to treat) based on the risk score. Based on the lowest estimated prevalence of pre-eclampsia of 3% and a test sensitivity of 93% and a test specificity of 97%, then to be 90% certain that the true specificity of the patient population is no less than 95%, a sample size of 4,800 participants is required. Thus, allowing for patient dropout, a study population of 5,000 women is needed.

Study Type

OBSERVATIONAL

Enrollment

5,000

Conditions

Pre-eclampsia Pregnancy

Eligibility

Sex: FEMALEMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Nulliparous. * Singleton pregnancy, between 9+0 and 16+6 weeks' gestation. * Signed informed consent. Exclusion Criteria: * Unsure of last menstrual period (LMP) and unwilling to have ultrasonography screening (USS) at ≤ 20 weeks. * ≥ 3 miscarriages. * ≥3 terminations of pregnancy. * Known or suspected major fetal anomaly/abnormal karyotype. * Essential hypertension treated pre-pregnancy. * Moderate-severe hypertension at booking (BP \>160/100 mmHg). * Diabetes mellitus. * Renal disease. * Systemic lupus erythematosus. * Anti-phospholipid syndrome. * Sickle cell disease. * HIV positive. * Hepatitis B or C positive. * Major uterine anomaly. * Cervical suture in situ. * Knife cone biopsy. * Long-term steroids. * Treatment with low-dose aspirin. * Treatment with heparin/LMW heparin. * Lack of informed consent. After recruitment, if the woman is found to be outside the stated gestation limits for the IMPROvED 1st visit of 9 weeks 0 days to 13 weeks 6 days she will be retained in the study if she is willing to take part in the second and third visit and is otherwise eligible. There is one pre-specified criteria for discontinuation of a participant. If a woman is recruited into the IMPROvED study and later identified as having a pregnancy exclusion criterion, i.e., ≥ 3 miscarriages, ≥ 3 TOPS, or using low-dose aspirin at the time of recruitment, she shall be excluded. However, women diagnosed during the pregnancy but after recruitment with an exclusion criterion, e.g., diseases such as renal disease, anti-phospholipid syndrome, etc. shall be retained within the study. Women who are recruited but later discontinue from the study do not count towards recruitment targets for each centre. Accordingly, such dropouts must be replaced.

Outcomes

Primary Outcomes

Pre-eclampsia.

Preeclampsia is defined as gestational hypertension defined as systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg (Korotkoff V) on at least 2 occasions 4h apart after 20 weeks' gestation, but before the onset of labour or postpartum systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg on at least 2 occasions 4h apart with either proteinuria ≥300mg/24h or spot urine protein:creatinine ratio ≥30mg/mmol creatinine or urine dipstick protein ≥++.

Time frame: 7 days after birth

Spontaneous pre-term birth

Spontaneous pre-term birth is defined as spontaneous preterm labour or preterm premature rupture of the membranes resulting in preterm birth at \<37+0 weeks' gestation.

Time frame: Up to 37+0 weeks´ gestation

Small for gestational age (SGA)

The birth weight is converted to a customized centile, adjusting for gestation, maternal weight, height, parity, ethnicity and infant sex. SGA is defined as \<10th customised centile.

Time frame: Within 24 hours after birth