Disscusion:
In the current study, we found that RHI values of women with pregnancies
complicated with placenta-mediated IUGR were significantly lower
compared with RHI values of pregnant women with normal intra-uterine
growth. The lower RHI values indicate systemic vascular dysregulation
and endothelial dysfunction.
Of note, although the median RHI value was significantly lower among
women in the IUGR group, the median RHI value in women with normal fetal
growth was also below the level defined as normal in the general
population. This finding is in correlation with previous studies that
assessed endothelial function in different stages during normal
pregnancy, and found that from the third trimester onward, there is a
gradually deterioration in endothelial function 2324.
Therefore, it is possible that there is a physiological decrease in
endothelial function during normal pregnancies. This finding may account
for the lack of significant difference in the rate of endothelial
dysfunction between the two groups, according to the definition used in
the non-pregnant population. Of note is the fact that despite the
physiologic endothelial dysfunction demonstrated in the control group,
the absolute lower RHI levels among women with IUGR pregnancies
indicates that endothelial function is impaired in women with
normotensive IUGR.
It is well established that women with preeclampsia exhibit endothelial
dysfunction both during pregnancy and years after delivery11,25,26. However, the data regarding IUGR pregnancies
without hypertension or preeclampsia are limited. Endothelial cell
activation markers were reported to be higher only in preeclamptic but
not in IUGR pregnancies, supporting the hypothesis that endothelial
dysfunction in IUGR pregnancies is confined to the uteroplacental
circulation and is not systemic as in preeclampsia 27.
On the other hand, Yinon et al. have showed that patients with previous
early onset placenta-mediated IUGR without preeclampsia had endothelial
dysfunction years after delivery similar to patients with previous
early-onset preeclampsia. Moreover, patients with previous IUGR had the
most severe degree of endothelial dysfunction even in comparison to
patients with previous preeclampsia 14. These findings
correlate with epidemiological data indicating increased risk for
cardiovascular disease in women who had pregnancies complicated by IUGR13. The findings of our study support the
aforementioned studies and show that endothelial function in women with
pregnancies complicated by IUGR is already impaired during pregnancy. It
is well known that multiple key angiogenic factors play a crucial role
in placental angiogenesis, amongst them are sFLT-1, sEng, VEGF and PlGF,
which coordinate to generate the placental villous tree, and abnormal
expression of these angiogenic factors will result in endothelial
dysfunction 2829. However, it is still unknown whether
maternal exposure to these angiogenic factors released from the ischemic
placenta during pregnancy result in endothelial damage and future
maternal vascular disease or whether endothelial dysfunction is a
preexisting condition leading to both placental dysfunction in pregnancy
resulting in preeclampsia and IUGR and to increased risk of future
cardiovascular disease later in life. We believe that our data support
the later theory in which maternal vascular dysfunction is a
predisposing factor leading to both abnormal placental development and
future cardiovascular disease. However, in order to prove this
hypothesis, it would be preferable to assess endothelial function prior
to conception.
Our finding of impaired endothelial function in women with pregnancies
complicated with IUGR may explain the increased risk of these women for
future cardiovascular disease. Therefore, intervention such as lifestyle
modification or prophylactic treatment may prove beneficial in reducing
long- term morbidity and mortality among these women.
The strength of this study lies in its prospective nature and the well
characterization of the study groups including patients with isolated
IUGR without hypertensive diseases. Only cases of IUGR that were
accompanied with abnormal umbilical artery Doppler flow were included,
thus ensuring that all cases of IUGR were due to placental
insufficiency. Moreover, to best of our knowledge, this is the first
study investigating endothelial function in IUGR pregnancies using the
EndoPATTM method. The main limitation of this study is
the small number of patients studied, which may limit our ability to
detect differences between the groups. However, despite the small sample
size, significant difference in RHI was found between the two groups.