Inflammation in Preterm Birth

Abstract

Preterm birth (PTB) is a worldwide health problem and remains the leading cause of perinatal morbidity and mortality. In South America, more than 10% of newborns are preterm, and the incidence is 10% in Uruguay. PTB is considered the final common pathway of different complications of pregnancy: infection, placental abruption, smoking, poor nutrition, alcoholism, multiple gestation, endocrine and coagulation disorders and fetal or maternal genetic susceptibility. Most of these involve an inflammatory cytokine-mediated response. Infection has been regarded as one of the most heralded causes of PTB due to the drastic link between underlying infectious agents and their ability to promote inflammatory responses. A strong explanation for initiation of distinct immune pathways is probably the activation of toll-like receptors (TLRs). TLRs are a diverse set of innate immune sentinel receptors of pathogens highly conserved throughout evolution. It is likely that differential uterine immune responses occur due to the diversity of pathogens that ensues activation of any one of the TLRs, ultimately leading to deleterious inflammation and preterm birth. In particular, TLR4 is wide expressed in different cell types of the placenta. Our group is investigating the association of diverse factors to preterm delivery. In the past 8 years we have been collected epidemiological data and tissue samples from mothers and newborns. TLR4 genetic variations (Asp299Gly) have been looked closely trying to associate SNPs to the commonly risk factors that contribute/cause PTB. Our results show that young mothers tend to have more preterm children than older ones. However, education level didn't affect the incidence of PTB. The smoking habit strongly associates to PTB. Hypertension, pregnancy bleeding, PPROM and intra uterine growth restriction (IUGR), clearly were linked to PTB. The association of hypertension, PPROM, bleedings, IUGR, and the smoking habit suggested the possibility of vasoconstriction and/or an altered liberation of cytokines as a common basis of the process that leads to premature labor. Since TLRs play a key role in those pathways and the Asp299Gly variation has been associated to a blunted response toward pathogens, an association of the SNP was expected. However, PTB was not linked directly to the presence of TLR4 variations. An exception was the association between severe PTB (less than 33 weeks of gestation), PROM and the presence of the AspGly variation suggesting possible differences between the pathogenesis of severe and moderate preterm birth. Interestingly; infection was not always present at detectable levels probably signifying that overproduction of cytokines can be harmful to the fetus because activation of the cytokine flow. We conjecture that an altered cytokine expression can cause per se preterm labor. Complications of PTB are associated with increase of medical expenses, representing billions of dollars of direct costs and unrealized potential each year , sometimes unaffordable for poor countries. On another hand individual and ethnic differences exist both in the prevalence of infection related preterm birth and in the extent of immune responses to infection. Variability in immune responses may influence the different levels of susceptibility in women to preterm labor. Social, genetic and demographic characteristics are probably unique to each population. In Latin American, risk factors associated to PTB remain poorly understood. In particular, more efforts should be done in order to unveil gene variants associated to PTB in these particular populations.