Inflammatory mediators
Outside of pregnancy, increased serum IL-6 and TNF-α has been reported
in patients with CH. In one study, the prevalence of hypertension was
double in those in the upper quartile of IL-6 and TNF-α when compared to
those in the lower quartile.18 Two smaller studies
further support a role for TNF-α in the pathophysiology of hypertension
by reporting elevated TNF-α in those with CH compared to those
without.19, 20 TNF-α has been shown to induce
structural as well as functional alterations in endothelial cells,
enhances the production of endothelin and other inflammatory mediators,
including IL-6 and VCAM, that ultimately lead to atherosclerotic plaque
formation and progression.12, 21 In addition, the
increases in serum IL-6, TNF-α, endothelin and VCAM have been correlated
to the degree of cardiovascular risk in patients with CH and, thus, have
emerged as predictors of cardiovascular morbidity.22
During pregnancy, there is extensive literature to support a 2-3 fold
increase in the production of IL-6, TNF-α, endothelin and VCAM in
pregnancies already complicated with PE.23, 24 It has
been proposed that, similar to outside of pregnancy, these inflammatory
mediators lead to the development of atherosclerotic-like
lesions.25 Within the feto-placental circulation,
these lesions result in placental hypoxia and, within the systemic
circulation, result in endothelial dysfunction and the maternal syndrome
of PE.26 However, it remains to be clarified as to
whether this inflammatory process predates the placental impairment or
whether it is a consequence of it.
Our work has demonstrated that, in women with CH, first trimester
alterations in IL-6 and endothelin exist. We have shown that women with
CH who are hypertensive have elevated first trimester serum endothelin
when compared to normotensive controls. Women in group 4 who are taking
antihypertensive medications are likely to have had a longer duration of
disease than those in group 1 who are previously undiagnosed. Along with
our findings, this supports the existing literature where a positive
correlation between levels of endothelin and mean arterial pressure but
not duration of disease has been demonstrated.23, 27
Endothelin is also known to increase the expression of other
inflammatory cytokines such as IL-6, another biomarker of endothelial
disease.13 The finding of lower first trimester serum
IL-6 for group 4 only when compared to normotensive controls was
unexpected. In normal pregnancy, current literature has demonstrated a
doubling in the maternal serum concentration of IL-6 when compared to
non-pregnant controls due to trophoblastic production in the early first
trimester.28 It has been suggested that IL-6 may have
a major role in the normal paracrine regulation of placental development
and hormone production.28 We propose that in women
with CH, particularly those with more severe disease as in group 4,
there is less capacity of the impaired placenta to up-regulate its
production of IL-6, as with sFLT-1. In contrast, first trimester
maternal serum concentration of endothelin is approximately halved when
compared to non-pregnant controls and is considered to be a protective
mechanism against its vasoconstrictive properties.29Thus, the endothelin levels measured are a reflection of maternal
systemic production rather than a trophoblastic contribution, as with
IL-6.