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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

Preterm birth remains a major unresolved problem in perinatal medicine. It is strongly related to increased perinatal mortality and morbidity, e.g. the risk of cerebral palsy is 70 times greater at delivery <28 weeks of gestation compared with delivery at term.1 Preterm birth is sometimes iatrogenic due to conditions such as severe intrauterine growth retardation or pre-eclampsia, and may be related to multiple pregnancies or to the presence of fetal malformations. A major proportion of preterm births occur spontaneously either with intact membranes or following preterm prelabour rupture of the membranes (PPROM).

The aetiology of preterm birth is complex but previous data indicate that infection/inflammation is important, especially in spontaneous preterm birth at very low gestation (<30 weeks).2

INFECTION/INFLAMMATION AND BIRTH

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

Microorganisms are believed to ascend from the lower genital tract, cross the cervical barrier and invade the decidua, chorioamniotic membranes, and amniotic fluid. In some cases the umbilical cord and the fetus are infected.3 Infection is accompanied by a host-inflammatory response, which involves accumulation of inflammatory cells in the chorioamniotic membranes and expression of cytokines in the fetoplacental tissues.2,3 Inflammation could trigger myometrial contractions, PPROM and cervical maturation leading to preterm birth. Such a sequence of events is supported by a strong association between increased cytokine levels (e.g. interleukin-6 [IL-6] and IL-8) in the amniotic fluid and preterm birth in women presenting with preterm labour or PPROM.4,5 There is also an association between the immuno-inflammatory reaction and neonatal morbidity, including bronchopulmonary dysplasia and cerebral palsy.6 Most of the studies addressing these issues have been performed in the USA and there are few studies available from northern Europe with transabdominal sampling of amniotic fluid.7

There are several important differences between a Scandinavian country, like Sweden, and North America. In Sweden, the incidence of preterm birth has decreased from 6.3% to 5.6% since the mid 1980s,8 whereas in the USA and many other countries, the incidence of preterm birth is significantly higher (12%) and has increased slightly from the 1980s to the mid 1990s.9 One possible explanation for the difference in incidence of preterm birth could be a lower number of women with infection-related preterm birth, as the rate of infection in the genitourinary tract (e.g. urinary tract infections, bacterial vaginosis [BV], clinical chorioamnionitis) and of neonatal sepsis appear to be comparatively low in Sweden.10–13

In order to investigate this possibility, a Swedish population of women (<34 weeks of gestation) in preterm labour and PPROM was examined.14,15

MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

The relationship between the intra-amniotic microbial colonisation and the levels of IL-6 and IL-8, and their relationship with preterm birth (delivery within 7 days and delivery at <34 weeks of gestation, respectively) was investigated.14,15 Microorganisms in the amniotic fluid were detected in 16% of women in preterm labour and 25% of women with PPROM. Such an occurrence of microbial colonisation is well within the range reported in the literature (preterm labour: median 13%, range 3–48%; PPROM median 34%, range 15–57%).2,6,14,15 There was also a high proportion of cases with preterm labour (43%) and PPROM (57%) which had elevated IL-6 and/or IL-8 levels in the amniotic fluid, indicating an inflammatory response. A strong association between inflammation, microbial invasion and preterm birth was found. Amniotic fluid cytokines predicted preterm birth (e.g. IL-6: sensitivity 83%, specificity 87%; IL-8: sensitivity 91%, specificity 87% in women in preterm labour) to a similar extent.2,4–6 Our group has also found in a new national population based study that the subgroups of preterm birth seem to be identical to populations with higher preterm birth rate, e.g. the lower frequency of perinatal infections does influence the composition of the preterm population.8,16

INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

More than 50 cytokines/chemokines are regulated in response to preterm labour/PPROM, but very little is known about the relative role of these proteins and how they interact in the process leading to preterm birth.2,4–6,17,18 Until recently, it remained unknown how the cytokine-driven inflammatory process was initiated. Over the past few years, it has been discovered that microorganisms interact with a family of toll-like receptors (TLRs) belonging to the innate immune system, which trigger intracellular activation of nuclear factor kappa B (NFκB) and various kinases, leading to the production and release of cytokines and anti-microbial peptides.19 Recent studies indicate that anti-microbial peptides are expressed in the endometrium20 and their production is induced after intrauterine infection in preterm and term pregnancies,21,22 offering indirect support for the involvement of innate immunity. Experimental data indicate that preterm labour depends on the expression of TLR-4, since pregnant mice deficient in this receptor are partly resistant to the administration of lipopolysaccharide (LPS).23

We have also found that systemic activation of TLR-4 through the administration of LPS has toxic effects on the immature CNS. As a result, LPS induces white matter injury in chronically-instrumented fetal sheep.24 In other animal models, LPS does not induce damage per se, but increases the vulnerability in response to secondary insults.25

INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References

Interleukin-18 (similar to IL-1β) is synthesised as a pro-form and is activated through cleavage by the enzyme caspase-1. It activates the NFκB intracellular signalling pathway through interaction with the IL-18 receptor resulting in the production of pro-inflammatory molecules, such as interferon-γ, tumour necrosis factor-α (TNF-α) and IL-1. Interleukin-18 has pleiotrophic qualities that regulate both the innate and acquired immune responses, which are important in the host defence against severe infections.26 As a result, IL-18 could be anticipated to play an important role in infection-related preterm birth.

We found that levels of IL-18 are significantly higher in both the cervical and amniotic fluid of women in preterm labour when compared with women who were not in labour at term.27 Levels of IL-18 in the amniotic fluid seemed to follow the pro-inflammatory cytokine pattern of response in preterm labour, with higher levels in cases with microbial invasion, and those delivering at <34 weeks of gestation or within 7 days of presentation in preterm labour. The response was very different in the PPROM group in which IL-18 tended to be higher in women with longer latencies.27

Interleukin-18 also activates apoptosis by enhancing Fas expression and participates in the cytotoxic response to LPS administration. A high level of IL-18 in the cord blood of preterm infants is associated with neonatal development of periventricular leukomalacia and cerebral palsy.28 We have recently found that IL-18 is markedly expressed in the immature rodent brain29 after various insults. The vulnerability of the CNS, particularly the white matter, was decreased in mice deficient in IL-18,29,30 providing support for the hypothesis that IL-18 could be an important factor in the fetal-inflammatory response syndrome and the subsequent risk of brain injury.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INFECTION/INFLAMMATION AND BIRTH
  5. MICROBIAL INVASION AND CYTOKINE RESPONSES IN PRETERM LABOUR/PPROM IN WESTERN SWEDEN
  6. INVOLVEMENT OF INNATE IMMUNITY IN PRETERM LABOUR AND CNS VULNERABILITY
  7. INTERLEUKIN-18: A ROLE IN PRETERM LABOUR AND BRAIN INJURY?
  8. References