IMproved PRegnancy Outcome by Early Detection

• Conditions: Pre-eclampsia; Pregnancy, High-risk; Pregnancy; Pregnancy Complications

• Registration Number: NCT01891240
• Lead Sponsor: Louise Kenny

Brief Summary

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.

Detailed Description

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 Timeline

• Study First Submitted: 2013-05-20
• Study First Submitted QC: 2013-06-27
• Study First Posted: 2013-07-03
• Study Start: 2013-11
• Status Verified: 2016-11
• Last Update Submitted: 2016-11-07
• Last Update Posted: 2016-11-08
• Primary Completion: 2017-10
• Study Completion: 2018-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 5000

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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Pre-eclampsia.	7 days after birth	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 ≥++.
Spontaneous pre-term birth	Up to 37+0 weeks´ gestation	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.
Small for gestational age (SGA)	Within 24 hours after birth	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.

Secondary Outcome Measures

Name	Time	Method
Early onset pre-eclampsia	Followed for the duration of hospital stay, an expected average of 6 weeks	Pre-eclampsia resulting in delivery at \<34+0 weeks' gestation.
Multisystem complications of pre-eclampsia	Between 20 weeks´gestation and 6 weeks after birth	Defined as one or more of the following: * Acute renal insufficiency defined as new increase in serum creatinine to \>100μmol/L antepartum or \>130μmol/L postpartum.; * Liver disease defined as raised aspartate transaminase and/or alanine transaminase \>45 IU/L and/or severe right upper quadrant or epigastric pain or liver rupture.; * Neurological problems defined as eclampsia, imminent eclampsia (severe headache with hyperreflexia and persistent visual disturbance) or cerebral haemorrhage.; * Haematological abnormalities including thrombocytopenia (platelets \<100x109/L), disseminated intravascular coagulation or haemolysis, diagnosed by features on blood film (such as fragmented cells, helmet cells) and reduced haptoglobin.
Pre-eclampsia with severe fetal or neonatal complications	Followed for the duration of hospital stay, an expected average of 6 weeks	Pre-eclampsia resulting in either delivery at \< 32+0 weeks' gestation or major neonatal morbidity or stillbirth or neonatal death or post-neonatal death.
Major neonatal morbidity in preterm infants	Followed for the duration of hospital stay, an expected average of 6 weeks	One or more of the following amongst babies delivered before 37 weeks' gestation: Grade III or IV intraventricular haemorrhage; Chronic lung disease; Necrotizing enterocolitis; Retinopathy of prematurity stage 3 or 4; Sepsis (blood or CSF culture proven); Or cystic periventricular leukomalacia. These conditions will be defined using the Australian and New Zealand neonatal network definitions.
Major neonatal morbidity in term infants	Followed for the duration of hospital stay, an expected average of 6 weeks	One or more of the following amongst babies delivered at or after 37 weeks' gestation: Grade II or III hypoxic ischaemic encephalopathy; Ventilation \>24 hours; Neonatal unit care admission \>4 days; Apgars \< 4 at 5 minutes; Cord arterial pH \<7.0 and/or base excess \>-15; Or neonatal seizures.
Pre-eclampsia with severe maternal complications	Followed for the duration of hospital stay, an expected average of 6 weeks	The development of pre-eclampsia with one or more of the following: Maternal death; Persistent severe hypertension (systolic blood pressure ≥170mmHg or diastolic blood pressure ≥110mmHg on more than one occasion antepartum or postpartum); Or multi-system complication (as defined in outcome above.
Early onset SGA	Followed for the duration of hospital stay, an expected average of 6 weeks	SGA resulting in delivery at \<34+0 weeks' gestation.
Preeclampsia with either severe maternal complication or severe fetal or neonatal complications	Followed for the duration of hospital stay, an expected average of 6 weeks	Pregnancies affected by severe maternal or severe fetal or neonatal complications (as defined in Major neonatal morbidity in preterm infants or Major neonatal morbidity term infants).
SGA with severe fetal or neonatal complications	Followed for the duration of hospital stay, an expected average of 6 weeks	SGA and either delivery at \<32+0 weeks' gestation or major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.
Spontaneous preterm birth with PPROM	Followed for the duration of hospital stay, an expected average of 6 weeks	Spontaneous PTB following preterm premature rupture of the membranes (PPROM).
Early onset spontaneous preterm birth	Followed for the duration of hospital stay, an expected average of 6 weeks	Spontaneous pre-term birth resulting in delivery \< 34+0 weeks' gestation.
Spontaneous preterm birth with severe fetal or neonatal complications	Followed for the duration of hospital stay, an expected average of 6 weeks	Spontaneous preterm birth (PTB) resulting in either delivery at \<32+0 weeks' or spontaneous PTB resulting in major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.
Spontaneous preterm birth without PPROM	Followed for the duration of hospital stay, an expected average of 6 weeks	Spontaneous PTB with intact membranes at the onset of labour.

Trial Locations

Locations (6)

Cork University Maternity Hospital, University College Cork; 🇮🇪 Wilton, Cork, Ireland

Erasmus Medical Center Rotterdam; 🇳🇱 Rotterdam, Netherlands

Karolinska University Hospital Huddinge, Karolinska Institute; 🇸🇪 Stockholm, Sweden

Liverpool Women's Hospital, University of Liverpool; 🇬🇧 Liverpool, Merseyside, United Kingdom

Keele University School of Medicine, Shrewsbury and Telford Hospital NHS Trust; 🇬🇧 Shrewsbury, Shropshire, United Kingdom

Keele University School of Medicine, University Hospital of North Midlands; 🇬🇧 Stoke-on-Trent, Staffordshire, United Kingdom