Cardiac- and vascular disease (-abnormalities) as underlying cause of premature birth.

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.
Usually, premature delivery is the consequence of preterm rupture of membranes
and/or premature labour. It is known that the growing fetus, the placenta and
the uterus 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 only.
Prematurity is an important cause of neonatal mortality and morbidity.

Recently it has become evident that maternal cardiovascular pathology is a risk
factor for premature delivery. Investigation of the placenta after premature
birth often shows vascular abberations of unknown cause. Additionally, pregnant
women with a congenital heart disease have an increased risk to deliver
prematurely.
This last finding is the basis of the ZAHARA3 project, where pregnant women
with a congenital heart disease are asked early in pregnany to participate in
this study where between 11 and 14 and again between 20 and 24 weeks of
gestation, fetal growth, the placenta and the uterine vessels that feed the
placenta are evaluated using Doppler ultrasound. In this study we investigate
if there are clinical markers that can also be used to predict premature
delivery in women without congenital heart disease. Additionally we collect
blood and urine at these timepoints.
The molecular biology part of the study investigates the development of
placenta and myometrium in mice with a congenital heart disease during
pregnancy. The molecular leads for diagnostics and theraphy of premature
delivery coming from these animal experiments will be validated on human
biosamples taken with informed consent during delivery of pregnant women with
congenital heart disease.

The PRELHUDE study investigates the reversed situation; whether subclinical
congenital heart defects or vascular pathology of the placenta and/or placenta
bed are present in women with idiopathic premature delivery.
It is important to investigate this. The detection of a subclinical hart defect
and treatment of this condition may improve long term health. Additional
molecular data on the nature of the placental vascular pathology may lead to
improved diagnostics and improved prognosis of a threatening premature
delivery. The identification of the genes involved in this process will benefit
the treatment of threatening premature delivery in future.

The PRELHUDE study investigates the reversal of the ZAHARA3 study; whether
subclinical congenital heart disease occurs in women who deliver prematurely
for unknown reason. The biosamples taken during and after delivery will be used
to determine vasular pathology in the placenta and the placenta-bed. Molecular
biology investigations of these tissues and myometrium will be aimed at
identifying the molecular basis of these aberrations and premature birth.

Pregnant women who present with threatening premature labour will be asked to
participate in the PRELHUDE study. In case of informed consent, women will be
included if they deliver prior to 37 weeks of gestation.

--> At the time of delivery, blood of mother will be drawn.
--> If the delivery is done by caesarean section, or if after delivery the
placenta has to be removed under anaesthesia, biopsies of the placenta-bed and
the myometrium will be taken.
--> After birth placenta biopsies and umbilical cord blood from the placenta
will be taken.
--> Within 72 hours after deliver, the cardiac status of mother is evaluated by
ECG and ultrasound.

The venapuncture infers minimal burden. The risks are the risks for any
venapuncture; sometimes a mildly sore spot or a hematoma.

The taking of myometrium and placenta-bed biopsies are considered a procedure
with minimal risk. The duration of the operation will be extended with a few
minutes and the taking of the biopsies will not contribute to bloodloss or
healing of the wound.

Placenta sampling and umbilical cord blood collection will be done postpartum
and do not infer risk or discomfort for mother or baby.

Within 72 hours after delivery an ECG and maternal cardiac ultrasound will ne
done. These procedures do not infer risk or burden for the patient.