Labor and Delivery myometrium and in-labor myometrium.53 IL-1β was predominantly located


in leukocytes, whose presence increased during term labor. Weak staining was also demonstrated in myocytes. IL-6 and TNF-α were restricted to leukocytes; from the morphological appearance of these leukocytes, they are likely to be neutrophils and macrophages respectively. Interestingly, IL-8 was observed infiltrating leukocytes in the laboring myometrium and not in the myocytes themselves; however, as discussed below, others have attributed increased levels of IL-8 in the laboring myometrium to the myocytes themselves.53


Whether the activation of inflammatory pathways in the myometrium is a cause or consequence of labor is debatable. Recent work by Bisits and colleagues has gone some way to addressing this.54


Using a novel


application of structural equations modeling, the mathematical plausibility of three commonly proposed pathways of myometrial activation was tested. These pathways were inflammatory stimulation, functional progesterone withdrawal, and oxytocin receptor activation. Data provided from quantitative reverse transcriptase polymerase chain reaction performed on key genes involved in these pathways were used to generate alternative causal pathways using mathematical formulae known as directed graphs. The data analysed from 12 non-laboring and 12 laboring women strongly supported inflammation as a primary driver of human myometrial activation for labor.


Nuclear Factor Kappa B as a Mediator of Labor Onset NF-κB is a family of transcription factors classically associated with inflammation that control expression of cytokines and chemokines—for example, TNF-α and IL-1β.55


The NF-κB family comprises five members:


NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-rel.56 Interactions between these members and their intracellular location dictate their function and ability to interact with DNA to promote the expression of inflammatory genes. Chapman and colleagues have previously reported the presence of all subunits except RelB and p52 in the myometrium. Although total RelA was found to be reduced in lower-segment myometrium in laboring women, DNA-binding activity was actually increased.57


NF-κB also appears to play a pivotal role in the transcriptional regulation of contractile associated genes in the myometrium and fetal membranes at the time of labor. COX-2, the rate-limiting step for prostaglandin synthesis, is elevated in lower-segment myometrium towards term58 in labor versus non-labor samples.59


and Work by our own group has


confirmed in vitro that NF-κB is required for IL-1β-induced expression of COX-2 in myocytes60


increases in myometrium with the onset of labor.61


and, consistent with this, that IL-1β concentration NF-κB also regulates


the proinflammatory cytokines IL-8 and IL-6, which both contain NF-κB recognition elements within their promoter regions.56 increased in laboring myometrium62


non-stimulated and IL-1β-stimulated myocytes in vitro.63 IL-8 is dramatically


and is detected in the supernatant of Transcriptomic


studies comparing myometrial biopsies from non-laboring versus laboring term women revealed that the largest differences were in IL-8 (47-fold increase with labor), IL-6 (14-fold increase), and IL-1β (11-fold increase).64 This study highlights the importance of proinflammatory genes in lower-segment myometrium in labor. We have also used microarray analysis on myocytes overexpressing p65 and showed that NF-κB regulates genes principally related to immunity and inflammation in these


106 cells.65 These studies, along with earlier work by Chan et al.,66 provide


evidence that the myometrium is capable of functioning as a distinct immune organ and that inflammatory pathways are critical components during parturition. Consistent with a proposed role in regulating labor onset, the administration of SN-50, an NF-κB inhibitor, in the amniotic fluid of mice was shown to delay pre-term birth.67


Immune Activation in Pre-term Labor Apart from gestational age, the outcome of pre-term labor and term labor is phenotypically similar.68


Both share a final pathway of cervical


ripening, uterine contractility, and rupture of membranes. Intuitively, this suggests that there is likely to be considerable overlap in the biochemical pathways leading to the final trigger of labor and expulsion of the fetus. Infection and/or inflammation are the only well-defined pathological processes at the molecular level in which a firm causal link with pre-term labor has been established.


As discussed above, immune activation and inflammation are physiological components of normal, term labor. We propose that, in events leading to pre-term labor, there is a pathological presence of inflammation, with or without infection, which precipitates cervical ripening, uterine contractility, and premature rupture of membranes. This may present as PPROM only, isolated uterine irritability or cervical dilation in the absence of contractions or PPROM, depending on the location of inflammation and/or individual patient characteristics.


Infection and/or Inflammation and Pre-term Labor One of the most common causes of inflammation is infection. In the context of pregnancy, approximately 30 % of pre-term deliveries are associated with an infective process.69


Upon review of the literature,


Goldenberg et al. summarised that 80–85 % of spontaneous pre-term labors at less than 28 weeks of gestation showed evidence of intrauterine infection, rising to over 90 % around 24 weeks, in contrast to around 15 % of women who delivered late pre-term at 34–36 weeks of gestation.70


Interestingly, the latter is a Gram-negative bacteria that can instigate inflammation through TLR4 signaling.72


The


most commonly identified pathogens associated with pre-term labor prior to rupture of membranes are Ureaplasma urealyticum and Mycoplasma hominis.71


Routes of transmission of


infection into the uterus and subsequently the fetus may be via hematogenous spread via the placenta, iatrogenic procedures such as amniocentesis or, as most commonly described, by an ascending route from the vagina through the cervix.73


The mechanism by which infection is able to trigger the parturition cascade is undoubtedly linked to an integrated network of interactions between the proinflammatory cytokines and prostaglandins. These act in concert to stimulate uterine contractions and remodel both the cervix and the fetal membranes, leading to cervical dilation and rupture of membranes, respectively.30,69


In response to intrauterine infection,


infiltrating leukocytes and decidual cells are capable of secreting the proinflammatory cytokines IL-1, IL-6, IL-8 and TNF-α.47,74,75


These cytokines


then induce prostaglandin production in the fetal membranes and decidua, leading to initiation of parturition.76,77


Although microbial infection is a common cause of inflammation, the presence of infection is not essential for inflammation-driven pre-term


US OBSTETRICS & GYNECOLOGY


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