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Cardiac- and vascular diseases (-abnormalities) as an underlying cause of premature birth.
PREterm Labour; Heart and vascular Defects.

Go to the PRELHUDE website.

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. It is defined as delivery before 37 weeks of gestation, and with a worldwide prevalence of 9.6%, yearly affects 12.9 million pregnant women. In the Netherlands, 14 thousand babies each year are born prematurely. Preterm birth is responsible for approximately 70% of all neonatal deaths and 40% of childhood neurological morbidities . Apart from the devastating effects of preterm birth on families, the financial costs to society are huge.
Two thirds of the preterm births occur as a result of spontaneous labour or preterm rupture of membranes. The initiating mechanisms behind this inappropriate early activation of uterine contractions and/or premature rupture of fetal membranes are unknown.
The relation between maternal CHD and premature labour is clearly established, but the opposite ‘women who present with idiopathic premature delivery may suffer from subclinical CHD’ has never been investigated. We will study if previously undiagnosed CHD is present in (apparently healthy) pregnant women with premature labour.
The second objective is to study and compare gene expression, protein expression and vascular histology in obstetrical biosamples in women with and without subclinical heart disease (as investigated through objective 1) who have delivered prematurely.


Study design
This study is an observational cohort study with invasive obstetrical biosampling.


Study population
The study will be performed in three collaborating perinatal centres, the AMC, UMCU and UMCG. We will study pregnant patients in preterm labour. The diagnosis of threatened preterm labour will be based on a combination of uterine contractions, measurement of cervical length, measurement of fetal fibronectin and possibly by the diagnosis of ruptured membranes.

Inclusion criteria:
All pregnant women presenting with signs of threatening preterm labour with a gestational age of 24 – 37 weeks, as defined by uterine contractions, at least 3 contractions per 30 minutes, and one of the following:
- Cervical length of ≤ 10 mm or
- Cervical length of 11-30 mm and a positive fibronectin test or
- Ruptured amniotic membranes
will be asked to participate in the study.
Patients are entered into the study if they indeed deliver < 37 wks of gestation.


Exclusion criteria:
• HIV positive patients
• Patients with known congenital heart disease


Patients in threatening preterm labour who are admitted will be asked to participate in the study. In case of delivery before the 37th week of gestation they will enter the study.
In case of a vaginal delivery, the placenta will be collected and 5 placental biopsies will be taken.
In case of delivery by caesarean section (expected to occur in a small percentage of patients) and in case of vaginal delivery and the need for general anaesthesia (for instance in case of a retained placenta) an additional 5 placental bed biopsies and one myometrium biopsy will be taken after delivery of the baby and placenta.
For both groups, maternal blood (12 ml) and umbilical cord blood (12 ml) will be collected to determine levels of for MMP-s, uPA and tPA that reflect activation of the coagulation cascade and that degrade type III collagen and fibronectin, both important components of the extracellular matrix next to the chorioamniotic membranes, and putatively relevant for premature preterm rupture of membranes that is an important clinical event in the progression to premature delivery.

After delivery, cardiac performance will be assessed within 72 hours. The investigations will consist of Doppler ultrasonography of the heart, with special focus on subclinical heart defects, such as valve insufficiencies/stenoses, septal defects and ventricular function. In addition, an ECG will be performed.


Outcome measures
Incidence of subclinical structural and functional heart defects in women who have delivered prematurely.


Power/data analysis
This is an observational study with invasive biosampling.
No data yet exist on the prevalence of CHD in patients who deliver prematurely. The target is a minimum of 150 patients.
There is scant information on the occurrence of subclinical heart disease in the general population. If we establish any structural heart defects, arrhythmias or conduction abnormalities in this group of women with idiopathic premature labour we will initiate a separate study to investigate 150 general healthy matched women who deliver at term to establish if findings are relevant for the occurrence of premature labour.


Time schedule
Inclusion starts March 2012.


Dr. C. Ris-Stalpers, UHD, staffmember department of Obstetrics and Gynaecology and reproductive biology laboratory, Academic Medical Center Amsterdam.


This project was funded by ZonMW


Dr. C. Ris-Stalpers, UHD, staffmember department of Obstetrics and gynaecology and reproductive biology laboratory, Academic Medical Center Amsterdam.