Endothelial dysfunction and pregnancy complications in women with congenital heart disease: an addendum to the ZAHARA-II study (ZAHARED study)

In the Netherlands, the population of at least 25.000 adult CHD patients is
rapidly increasing due to the surgical
progress made in the last decades, which has improved long-term outcome.
Pregnancy and fertility are important
issues in everyday practice of the grown-up congenital heart disease
cardiologists. The retrospective ZAHARA I
study (Zwangerschap bij Aangeboren HARtAfwijkingen = Pregnancy in Congenital
Heart Disease Study, showed an increased incidence of cardiac, obstetric and
fetal/neonatal complications in pregnant women with CHD. However, this
retrospective study provided no detailed (such as echocardiographic,
neurohumoral) data concerning the impact of the hemodynamic burden of pregnancy
on the diseased maternal heart. Therefore identification of high risk
pregnancies is up till now insufficient. In the proposed study we have the
unique opportunity to prospectively investigate the underlying mechanisms that
determine the occurrence of cardiac, obstetric and fetal/neonatal pregnancy
complications.
in addition to the abovementiond, Endothelial dysfunction (ED) plays an
important role in the pathophysiology of Pre-eclampsia and other pregnancy
complications. In the ZAHARA II study, a prospective multicentre ICIN study
supported by the Netherlands Heart Foundation (NHS2007B75), we will study the
changes in cardiac parameters (i.e. Nt-pro-BNP, echocardiography) as well as
the changes in uteroplacental flow parameters in 160 pregnant women with CHD
and in 60 healthy controls, and relate these to the occurrence of cardiac,
obstetric and neonatal complications. This will give insight in the underlying
mechanisms that determine the occurrence of pregnancy complications, thus
improving risk stratification and counselling of CHD women. We hypothesize that
ED occurs more frequently in pregnant women with CHD than in healthy pregnant
women and is associated with the increased occurrence of obstetric and neonatal
complications that is found in CHD women. ED may be related to underlying CHD
and to cardiac function.

Primary Objectives: To prospectively investigate the changes in cardiac
parameters (echocardiography, NT-pro-BNP) and uteroplacental flow (pulsatility
index, diastolic notching) during/after pregnancy in women with CHD and compare
these changes with with age/parity-matched healthy controls.
To relate the cardiac parameters (prepregnancy and during pregnancy) with the
occurrence of cardiovascular, obstetric and neonatal complications.
To relate the cardiac parameters (prepregnancy and during pregnancy) and
uteroplacental flow measurements with the occurrence of obstetric complications
and neonatal complications.
Secondary Objective(s):
To elucidate the mechanisms behind the increased incidence of obstetric and
neonatal complications in CHD patients by focusing on changes in
utero-placental perfusion.
To evaluate the incidence of permanent (1 year) decline of exercise tolerance
in women with CHD and compare this with healthy women.
To evaluate the risks scores for cardiac and neonatal complications in pregnant
women developed by Siu et al and by the ZAHARA1 investigators prospectively in
women with CHD.
To continue the (worlds largest) registration (ZAHARA registration) of
pregnancy outcome in CHD women, primarily to facilitate the future assessment
of long-term effects of pregnancy on survival and morbidity in CHD patients.

Prospective multi-center cohort study. All pregnant patients with a congenital
heart anomaly presenting before 20 weeks of gestation in the participating
medical centres will be asked to participate by their cardiologist. Data
concerning underlying heart disease/obstetric medical history will be retrieved
from medical records. In the participating centers it is common practice to
perform echocardiograms in CHD patients yearly/2-yearly, therefore prior
echocardiograms will be
available in most patients. Currently standardised outpatient follow-up
(including standardised echocardiograms)
are being developed by the Dutch 'Werkgroep Congenitale Cardiologie bij
Volwassenen' to improve uniformity.
Serial (20, 32 weeks of pregnancy, 1-year postpartum) standardised
echocardiograms will be performed. Foetal
growth and utero-placental perfusion (e.g. flow velocity measurements of
uterine and umbilical artery) will be
studied by Doppler ultrasound evaluations (20, 32 weeks; for healthy control
women only at 20 weeks). Neurohumoral parameters (Nt-pro-BNP) will be assessed
during/after pregnancy. Data concerning pregnancy complications will be
collected. Exercise testing will be performed 1-year postpartum in patients who
had undergone this test less than 1 year before pregnancy. It is estimated
based on the ZAHARA I study that 160 women with CHD and 60 healthy pregnant
controls will be enrolled during a 3-year period.

In this selected patientgroup of pregnant women with a congenital heart
anomaly, the number of study assessments are kept down to a minimum:
20 weeks, 32 weeks, 1 year post partum: Standardised echocardiography;
NTpro-BNP
20 weeks, 32 weeks: foetal ultrasound evaluation of intra-uterine growth and
amniotic fluid volume, obstetric
clinical evaluation. Uteroplacental Doppler flow registration
20 weeks, 32 weeks:totaal eiwit in 24uurs urine
20 weeks, 32 weeks: biomarkers for endothelila function
32 weeks: IMT measurement
1 year post partum: In the subgroup of patients who had pre-pregnancy exercise
testing, an exercise test will
be performed (preferably VO2max).
The proposed study assessments are risk-free.

For control women:
20 weeks, 32 weeks, 1 year post partum: Standardised echocardiography;
NTpro-BNP
20 weeks, 32 weeks: biomarkers for endothelila function
32 weeks: IMT measurement
20 weeks, 32 weeks:total protein in 24h urine
20 weeks: foetal ultrasound evaluation of intra-uterine growth and amniotic
fluid volume, obstetric
clinical evaluation.
20 weeks, 32 weeks: Uteroplacental Doppler flow registration


In zwangerschap op 20 + 32 weken: 24-uurs urine voor de bepaling van totaal
eiwit