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.