Inflammatory mechanisms are clearly implicated in all of
these insults, but how these channel both infectious and sterile
triggers has remained elusive. Also, how the cascade of preterm
birth overlaps with normal birth isn’t clear, mainly because the
biological processes of normal birth are not fully understood.
In the past, research has focused on improving outcomes
for the infant, such as the use of glucocorticoid drugs before
birth to mature the fetal lungs.
However, the ultimate goal is to prevent premature birth, and
to date there are no drugs or interventions that are very successful
in slowing or arresting preterm labour. Although tocolytic
agents that stall uterine contractions have shown promise, their
use is contentious and they may even harm the fetus since
prolonged exposure to high inflammatory mediators can damage
the fetal brain.
The problem with many of these drugs is that they target
what is effectively the last phase of the labour process. They
do little to slow the inflammatory response that drives labour
forward.
In theory, agents that target the initiating events of preterm
labour should be more effective than the inhibitors of uterine
activation that are currently used. An additional benefit of
targeting events at the top of the inflammatory pathway would
be to reduce the exposure of the fetal brain to inflammatory
damage.
Pharmacological inhibitors of inflammatory cytokines are one
prospect, but blocking signals upstream of these would be an
even better strategy. Reaching this goal requires a complete and
detailed understanding of the signals involved in initiating
preterm labour, particularly the point at which different trig-
gers converge, and how these relate to the events of normal
term labour.
It’s commonly believed that term and preterm labour are
fundamentally the same process that share a common pathway.
In the case of term labour, a series of activation events gain
momentum over several days and weeks to ultimately cause
uterine muscles to develop the ability to contract. The same
underlying events cause the cervix to soften and relax, allowing
the fetal head to pass. Preterm labour is believed to result when
pathological processes prematurely activate one or more compo-
nents of the same common pathway.
The major knowledge gap lies in defining the critical acti-
vators in term labour and the point at which this pathway is
usurped in preterm labour. Human clinical data is limited since
cause and effect relationships are extremely difficult to estab-
lish without experimental interventions. Fortunately, many
key features of human childbirth are evident in rodents and
sheep models.
It’s now emerging from mouse studies that bacterial infec-
tion induces preterm delivery by increasing inflammatorycytokines that recruit immune cells to the uterus and stimulate
contractions. The cytokine IL6 accelerates the inflammatory
cascade in both term and preterm deliveries, while IL6 defi-
ciency delays birth. Other cytokines, such as IL10, are nega-
tive regulators, with genetic IL10 deficiency predisposing to
infection-induced preterm delivery. These animal studies provide
an explanation for how subtle DNA changes in cytokine genes
in women might influence their susceptibility to preterm
delivery.
However, not all preterm births are caused by infection:
toll-like receptors (TLRs) are another key mediator of the birth
process. TLRs are abundant in the maternal uterine and
placental membranes, and elicit inflammatory cytokines when
stimulated.
One particular form, TLR4, appears to be a key mediator
of childbirth that can be activated by bacteria as well as during
normal cellular processes. Mice with a natural mutation in the
TLR4 gene, or that are modified to be deficient in TLR4
signalling, do not experience infection-associated preterm
delivery because the induction of inflammatory cytokines,
leukocyte recruitment and uterine activation fail to occur.
Strikingly, these TLR4-deficient mice also have delayed
timing of normal birth and a high rate of fetal death at the time30 | JAN/FEB 2016
It’s now emerging from
mouse studies that
bacterial infection induces
preterm delivery by
increasing inflammatory
cytokines that recruit
immune cells to the uterus
and stimulate contractions.herjua/iStockphoto