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2002; 10 (1): 35-40


Iolanda Elena Blidaru1, Maria Stamatin2

University of Medicine and Pharmacy Iasi

Departments of Obstetrics and Gynecology1 and Neonatology2

Abstract. Preterm labor is the final common pathway after several potential insults to the feto-
maternal unit. As a common cause, intrauterine infections (both clinically evident and
subclinical) are associated with increased proinflammatory cytokine concentrations in the
amniotic fluid and the gestational tissues. This fact represents the trigger for the intrauterine
inflammatory response syndrome as an abnormal maternal immune response.
Key words: preterm birth, preterm labor, maternal immune response, cytokines

Rezumat. Naterea prematur este modalitatea final i comun de rspuns a unitii feto-
materne fa de multiple posibile injurii. Infeciile intrauterine (clinice i subclinice) sunt o
cauz frecvent i se asociaz cu creterea concentraiilor citokinelor proinflamatorii n lichidul
amniotic i esuturile gestaionale. Aceasta reprezint mecanismul declanator al sindromului
reacional inflamator intrauterin ca manifestare a unui rspuns imun matern anormal.
Cuvinte cheie: natere prematur, travaliu prematur, rspuns imun matern, citokine

INTRODUCTION delivery and consequently higher rates

Although ongoing advances in the of infant mortality.
fields of obstetrics and neonatology Beside that, there is an important
have resulted in significant improvements economic impact of prematurity upon
in pregnancy outcomes, solutions to the costs of the resources used to care
the problem of preterm labor and for the newborn children, because a
preterm birth remain frustratingly proportionally small number of births
unsolved. consume more than one third of
The high incidence of preterm birth, health-care expenditures during the
that continues unabated all over the first year of life. Moreover, due to the
world (1) and in our country, still sometimes- unfavorable long-term
represents a problem for the health outcomes, additional expenditures for
cares. developmental handicaps are necessary
Another facet of the problem is that during the remainder of childhood for
the prematurity represents the most many infants.
frequent cause of death in infancy, Despite of all medical advances and
nowadays when infant mortality has social efforts, the incidence of preterm
become a benchmark for international birth in the United States (e.g.) has
comparisons of health-care systems. risen from 9.4% of all deliveries in
The countries with large urban 1981 to 11% in 1993, with 83% of all
population or where poverty is neonatal deaths associated with
common have higher rates of preterm delivery at less than 37 weeks and two

Iolanda Elena Blidaru, Maria Stamatin

thirds occurring in the newborns final common expression that being

delivered at less than 29 weeks (2). uterine contractility.
In Iai county, at the Cuza-Vod This review focuses on the role of the
Maternity Hospital, the frequency of immune system as mediated by
preterm deliveries decreased from inflammatory cytokines in preterm
11.6% (1992) to 6.98% (1998) labor in its interdependence with
increasing again to about 9 percent in endocrine and paracrine systems.
the last three years. The mortality rate
for the premature newborns has CYTOKINES AT THE FETO-
fluctuated between a minimum of MATERNAL INTERFACE AND
51.61% (1999) and a maximum of THEIR ROLE IN PRETERM LABOR
81.8% (2000) from the total number of The traditional explanation for the
neonatal deaths. onset of parturition in the presence of
Considering these arguments, it infection has been that the microorganisms
becomes evident that the main goal of or their endotoxins directly stimulate
management is to prevent or arrest the prostaglandin biosynthesis. However,
preterm labor, but despite the because only few cases of preterm
introduction of tocolytic drugs, little labor may be attributed to clinically
progress has been made in this respect evident intrauterine infection and there
over the past 30 years (3). This lack of is an overlap of endotoxin concentrations
progress actually reflects a poor among groups with and without labor,
understanding of its pathophysiology the involvement of other factors was
and the need of a new approach. suggested. It has now been established
The preterm parturition may be that endogenous cytokines mediate in
considered as a response of the feto- the triggering the onset of preterm birth.
maternal unit to a variety of insults Defined as regulatory proteins secreted
such as: chorioamnionitis, ischemia by nucleated cells, the cytokines act as
(as in placenta praevia or abruptio, communication signals between
placental insufficiency), uterine different types of leukocytes and as
abnormalities (malformations, myomata, modulators of inflammatory responses
cervical incompetence), certain pregnancy (4). Their main characteristics are:
complications (overdistention due to - cytokines are simple polypeptides or
multiple gestation, polyhydramnios) or glycoproteins with a molecular weight
individual conditions (age, systemic < 30 Kd;
diseases, unfavorable environmental - basal production of cytokines is
or socio-economic state). usually low or absent, being induced
An important and more recently by various stimuli at the level of
achieved concept is that preterm birth transcription or translation;
represents a heterogeneous syndrome -cytokine production is transient and
(4) with many possible etiological typically autocrine or paracrine;
aspects, which is determined by - most of their actions are the result of
certain abnormalities in the maternal an altered pattern of gene expression in
immune response, leading to a single the target cells, leading to a modulation in

the rate of cell proliferation, a change in cell maternal, fetal and placental
differentiation status and/or change in compartments. Once activated by
the expression of some differentiated microorganisms, bacterial products or
functions; a dysregulation of the maternal
-although an individual cytokine may immune response, they secrete a wide
present a broad and diverse category range of inflammatory cytokines.
of actions, at least part of these The cytokines, which play a key role
manifests towards the immune cells. in mediating the inflammatory
One of the main sources of cytokine process, may be classified by their
production is represented by the general activity (5), as it is shown in
macrophages that are present in the Table 1.

Table 1. Inflammatory cytokines classified by activity

Class Cytokine
Oncostatin M
Anti-inflammatory TGF-

After stimulation, macrophages and the -chemokines, a class of cytokines

other damaged cells secrete that attracts and activates mainly
proinflammatory cytokines, which act neutrophils, while MIP-1 represents
to initiate the process. Interleukin-1 the -chemokines, that attract and
(IL-1) and tumor necrosis factor activate predominantly monocytes and
(TNF ) are the representatives for macrophages. Chemokines play
these cytokines (6, 7). They stimulate together the role to attract the immune
prostaglandin production and have effector cells and to induce their
other systemic and local effects, one activation (8).
of these being induction of the After this phase of initiation of the
chemokine or chemoattractant inflammatory process, immuno-
cytokine production. Among the over modulatory cytokines are produced.
20 characterized chemokines, the 2 IL-6, as a representative, but also
best-described ones are IL-8 and leukemia inhibitory factor (LIF), IL-
macrophage inflammatory protein 1 11 and oncostatin M act through
(MIP-1). IL-8 is the representative for multimeric receptor complexes,

Iolanda Elena Blidaru, Maria Stamatin

exerting a variety of effects which IL-6, IL-8, and MIP-1 (14). Although
depends on the context of activity, it is difficult to extrapolate the in vitro
amount of cytokine and the stage of data, it has been noted that decidual
differentiation of the target tissues (9). cells produce only relatively small
For example, IL-6 may enhance T and amounts of IL-10 (15).
B cells maturation, mediates the acute Similarly, fetal chorionic cells have
phase response and enhances been reported to produce important
prostaglandin secretion and the effect quantities of IL-6, IL-8, and MIP-1,
of chemokines. as a response to IL-1, TNF-, and
Anti-inflammatory cytokines, such as certain bacterial products as
IL-4, IL-10 and transforming growth lipopolysaccharide. IL-10 is also
factor (TGF ), with its many produced in small amounts and only as
species, mediate the resolution of a response elicited by the
inflammation. Originally termed lipopolysaccharide. Conversely, amniotic
cytokine synthesis inhibitory factor, cells supply only small amounts of IL-
IL-10 essentially acts by turning off 8 and other cytokines, but they have
the gene promoters for the most if not been demonstrated to produce more
all of the proinflammatory cytokines, arachidonic acid metabolites than
including IL-1, TNF-, IL-6 and IL-8. inflammatory cytokines.
IL-10 and TGF are critical both to The production of arachidonic acid
the normal healing and the normal metabolites by gestational tissues as a
evolution of pregnancy (10, 11). response to pro-inflammatory cytokines
The role of inflammatory cytokines in actually represents the key link from
the pathogenesis of preterm labor is cytokine cascade to preterm labor and
supported by the studies in the birth. IL-1, TNF- and IL-6 elicit
amniotic fluid, in vivo and in vitro production of the powerful uterotonic
gestational tissues and animal models. prostaglandin E2 by the human
Elevated amniotic fluid titers of many gestational tissues, including decidua
cytokines including IL-1 (12), TNF- chorion and amnion, thus inducing the
, IL-6, IL-8, MIP-1, and IL-4 (13), preterm birth.
have been associated with infection- Investigation of tissues obtained from
induced preterm labor, while the women experiencing preterm labor
findings about IL-10 concentration are and birth revealed that messenger
controversial. ribonucleic acid of inflammatory
Gestational tissues are other important cytokines including IL-1, TNF-, IL-
sources of cytokines at the feto- 6 and IL-8 could easily be isolated
maternal interface level, producing a from chorion and decidua, regardless
wide variety of cytokines after of the presence of infection (17), while
stimulation by bacterial products or IL-10 messenger ribonucleic acid was
pro-inflammatory cytokines. not found so universally (15).
Both explants and monolayer cultures Studies on animal models (mice, rabbits
of maternal decidua have been and primates) have demonstrated
demonstrated to produce IL-1, TNF-, consistent results. Moreover, the

attempt to stop labor by using Maternal gestational tissues are

immunotherapeutic agents was with constantly in contact with vaginal
no effect, suggesting that after the bacterial flora, but only few
cytokine cascade has been initiated the women have preterm birth,
normal inhibitory influences on the because the maternal immune
inflammatory process are not efficient. response, rather than the infection,
mediates the preterm labor.
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