Doppler Modifications in Intrauterine Growth Restricted Fetuses

The fetal heart is the central organ in fetal adaptive response to placental
insufficiency in prenatal life. Fetal growth restriction (FGR) is associated
with several cardiovascular changes involving preload, afterload, ventricular
compliance and myocardial contractility and it is well known that in the growth
restricted fetus cardiac output is redistributed from right to left ventricle *
the so-called *Left dominance* of the FGR fetus. These functional and
morphological changes ( *Cardiac Remodeling*) can be assessed using
echocardiographic parameters. In fact, several studies demonstrated an
impairment of these parameters in FGR fetuses . Despite that, while several
studies have been published about the modification of Doppler parameters of the
peripheral circulation in FGR fetuses following antenatal steroids (AS), to the
best of our knowledge no study has been published about the modification of
fetal functional echocardiographic parameters after corticosteroids in these
fetuses.
Steroids have to pass the placenta to reach the fetus. The placenta regulates
high cortisol levels in the fetus. Several genes are involved in fetal growth
and may be affected by AS. The HSD11B2 gene for example codes for the 11-*
hydroxysteroid dehydrogenase type 2 enzyme. This enzyme converts active
cortisol into inactive cortisone in the human placenta. It is a regulatory
mechanism to prevent the fetus from high intra-uterine cortisol levels. DNA
methylation is an epigenetic change of the DNA; a methyl group is coupled to a
cytosine molecule followed by a guanine molecule (CpG island). DNA methylation
might have impact on transcription of genes and cellular function. DNA
methylation is the best studied epigenetic process in relation to pregnancy
outcomes and fetal programming.In a recent study methylation of the HSD11B2
gene is related to lower birth weight and has impact on neurobehavioral
outcome. In another recent study, methylation of the HSD11B2 gene is related to
social economic adversity. In FGR fetuses receiving AS, methylation of the
HSD11B2 gene and other genes might have impact on the extent to which the
modification of fetal hemodynamical parameters change.

As altered methylation of the HSD11B2 gene will result in altered levels of
steroids in the fetal circulation, altered methylation most likely also
influences fetal immune characteristics. Higher levels of cortisol could cause
fetal immune activation and inflammation. This immune activation of a
vulnerable and developing fetal immune system could cause skewing of the fetal
immune system, and could for example cause a more allergy prone immune
phenotype. It could furthermore be hypothesized that in an immune associated
pregnancy complication as FGR, the fetus is more prone to immune modulation.
Besides the effects the steroids have on the fetal immune system it is
reasonable to expect effects on the maternal immune system. As the maternal
immune system is already challenged during pregnancy by the tolerance of the
semi-allogenic fetus, steroids will most likely also skew the maternal immune
system.
Our hypothesis is that fetal hemodynamical parameters change in FGR fetuses
after AS, and this process is influenced by methylation of the HSD11B2 gene in
the placenta.
We furthermore hypothesize that the degree of methylation of the HSD11B2 gene
influences the effect of maternal steroid administration on fetal immune
responses. This will be furthermore influenced by maternal immune parameters.

Primary Objective: To assess the hemodynamical effects of administration of AS
in FGR fetuses and to compare these effects with those that occur in
appropriate for gestational age (AGA) fetuses.

Secondary Objective(s):
To investigate the effect of methylation of the HSD11B2 gene and other genes in
relation to hemodynamical changes in FGR fetuses after AS compared to AGA
fetuses.

To investigate the effects of methylation of the HSD11B2 gene to fetal immune
characteristics.

To determine the intra- and interobserver reliability of the myocardial
performance index (MPI) on the Voluson E8 (GE Medical Systems, Zipf, Austria).

Prospective cohort study design

All patients are already admitted on the Obsterical department because of the
fetal growth restriction or other reason to administer antenatal steroids.
Ultrasound investigation will be devided in four sessions of 30 minutes. No
invasive procedures will take place.
Ultrasoud investigation is considered to be without risks for the pregnant
woman or her fetus.