The identification of novel markers for premature birth based on the investigation of pregnant women with congenital heart disease.

Delivery before the 37th week of pregnancy is premature and with a prevalence
of 9.6% this yearly affects about 14 thousand neonates in the Netherlands.
Prematurity is the leading cause of neonatal mortality and morbidity and is
strongly associated with delayed neurological- and motor development during the
first years of life.
Usually, premature delivery is the consequence of preterm premature rupture of
membranes and/or premature labour. It is known that the growing fetus, the
placenta and the myometrium contribute to the initiation of parturition but the
molecular mechanism that initiates labour is not known and there are no
prognostic markers available. Treatment can delay delivery for a short time,
probably because the events initiating labour occured weeks before. If active
labour has started, this process can not be reversed.
Detailed knowledge on the molecular events in placenta and myometrium and the
interaction between these tissues that initiate parturition, is essential to
develop prognostic tests and rational treatment.

The prevalence of idiopathic premature delivery is increased in women with
congenital heart disease. The overall prevalence is 16% with excesses to 30% in
case of complete transposition of the great arteries or pulmonary atresia with
ventricular septum defects. The undelying molecular hypothesis is that the
cardiomyoctes and the uterine myocytes contain a number of similar pathways and
mechanisms, that can be disregulated in pregnant women with congenital heart
disease who deliver prematurely.

Because pregnant women with congenital heart disease
1. go to the clinic relatively early in pregnancy,
2. are closely counselled to diagnose and if possible treat additional cardiac
complications of the mother or heart disease of the developing fetus,
3. have a relatively high chance of developing preterm premature rupture of
membranes and/or premature labour,
non-invasive tests during pregancy and biobanking of tissue samples in this
patient group offers the opportunity to develop prognostic tests and rational
and effective therapeutics that are important to diagnose and treat prematurity
in general.

1. To obtain early diagnostic and prognostic markers for preterm premature
rupture of membranes and premature labour, based on ultrasound examinations of
mother, placenta and fetus and markers present in blood and urine of mother at
11-14 weeks and 20-24 weeks of gestation.

2. To obtain a durable biobank containing placenta, placenta-bed and
myometrium, combined with a clinical database. The tissues will be used to
detremine the differences tissue specific expression that relate to the
abovementioned obstetrical complications.

The study is observational.
In case of informed consent
1. ultrasound examinations of mother, placenta and fetus will be done and at
the same time blood and urine samples will be taken. All samples will be stored
in the ZAHARA3 biobank.
2. placental biopsies will be taken after delivery as well as a myometrium and
placenta-bed biopsies in case of delivery by caesarean section and all these
samples will be stored in the ZAHARA3 biobank. Feasibility of biosampling will
be decided on by the obstretrician perfoming the operation.
Ultrasound data, clinical data on mother, the course of pregnancy and the
pregnancy outcome will be stored in a clinical database. The tissue samples
will be used to investigate RNA and protein profiles.

Ultrasound testing during pregnancy is a normal routine in this patient
population. Ultrasound examination of cervical length and utero-placental flow
is usually not done at these gestational ages, but will be done in the current
study. The Doppler-ultrasound evaluations will not infer additional risk or
discomfort for the patient.
The venapuncture infers minimal burden. The risks are the risks for any
venapuncture; sometimes a mildly sore spot or a hematoma.
The collection of a urine sample is without discomfort or risk.
The placenta sampling will be done postpartum and does not infer risk or
discomfort for mother or baby.
The taking of the myometrium and placent-bed biopsies are considered a
procedure with minimal risk. The duration of the operation will be extended a
few minutes and the taking of the biopsies will not contribute to bloodloss or
healing of the wound.