In spite of a large amount of research in recent years, the
mechanisms underlying physiological pregnancy and their changes which
trigger pathological conditions are not completely understood. However,
a strong correlation between the features of the inflammatory response
and the adverse outcomes of pregnancy has recently been found. Indeed,
inflammation is able to subvert the physiological changes that regulate
placental perfusion and myometrial tone. Further investigation into the
molecules involved in physiological and pathological pregnancy should
pave the way to their use, as well as that of their agonists and
antagonists, as therapeutic agents. From this perspective, control of
the maternal inflammatory response and its influence on vascular and
myometrial functions can be accomplished by administration of
progesterone and glucocorticoids. Indeed, it has already been
established that these hormones influence Th1/Th2 balance in early
pregnancy by inhibiting Th1 response, thus favouring anti-inflammatory
cytokine production [99,100].
It is also known that, in cases of recurrent pregnancy loss, a Th1
milieu which increases peripheral NK cell number and infiltration of
such cells in the endometrium is formed [12,101].
Furthermore, it has recently been demonstrated that glucocorticoids at
doses equivalent to those which enhance fetal lung maturity inhibit
pro-inflammatory cytokine production in explants from normal and
preeclamptic placenta, without altering anti-inflammatory cytokine
release [102].
In addition, it has been observed that, at least in mice, progesterone
action is exerted through an interaction with glucocorticoid receptors
and that corticosterone is 10–100 times more effective than
progesterone [99].
However, while progesterone is currently employed as a therapeutic tool
during early gestation, the use of glucocorticoids is generally still
restricted to the prevention of neonatal respiratory distress syndrome,
necrotizing enterocolitis and other severe third trimester
complications. The reasons for such a clinical attitude are not clear.
They may be due to a deeper concern about the teratogenic effects of
glucocorticoids compared with progesterone. Corticosteroid treatment
has been found to be ineffective in recurrent pregnancy loss associated
with autoantibodies [103].
However it has been reported that low doses of glucocorticoids are not
only harmless but even effective in the protection of pregnancy in
cases of recurrent abortion of unknown origin [104].
Such efficacy is confirmed daily in our clinical experience. Moreover,
recent reports indicate a beneficial effect of preconceptual
prednisolone treatment on the outcome of pregnancy in women with
history of unexplained recurrent abortion and characterized by elevated
levels of NK cells within the endometrium before treatment. In all of
these cases, NK cells are reduced upon prednisolone administration [105-107]. Knowing that uNK recruitment is a hormonally-controlled maternal function [10],
and that an increased number of these cells is associated with
recurrent miscarriage, NK cell cytotoxicity may well represent part of
the mechanism by which conceptus rejection takes place. This concept
should favour administration of low glucocorticoid doses with a view to
preventing sporadic and recurrent abortion, a philosophy currently
applied in our clinical practice, which urgently requires extensive
investigation. Indeed, it can be speculated that while progesterone is
needed in order to prepare the endometrium for the earliest phase of
implantation, the subsequent stages of placentation depend on adequate
maternal glucocorticoid production, aimed at controlling the factors
involved in the inflammatory response which occurs naturally in any
tissue remodeling. Based on the above considerations, the
administration of glucocorticoids in early pregnancy could be useful to
induce the appropriate maternal cytokine environment. Such a role of
corticosteroids in securing pregnancy from inflammatory wastage is
further enforced by the evidence that mifepristone, a drug employed to
induce medical abortion, is a potent antiglucocorticoid [108].
In light of the recent demonstration that some antibiotics, such as ampicillin, reduce amniotic PGE2 [109,110] and IL-6 release both in vitro and in vivo [111],
by a mechanism independent of their antibacterial properties, their use
in the management of the feto-maternal inflammatory state should also
be considered. Based on the detrimental role of TXA2/PGI2-imbalance
in the pathogenesis of preeclampsia, a further therapeutic strategy
could be represented by the administration of specific prostanoid
blockers, such as pirmagrel, a strong inhibitor of thromboxane
production in normal and preeclamptic cytotrophoblast [112].
In addition, the clinical benefits of heparin and aspirin in cases of
poor pregnancy outcome, such as antiphospholipid syndrome, are also
recognized. The use of low doses of these drugs in the management of
early pregnancy dysfunction is justified by their influence on EVT
differentiation [113] and apoptosis [114].
Finally, considering that inflammation and oxidative stress are
features of preeclampsia, a combination of low-dose aspirin and
antioxidants like vitamins C and E has been advocated in management of
the syndrome, although the possible benefit of such a therapy is still
awaiting adequate clinical investigation [95].
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