Introduction and epidemiology by lnd15050

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									The Spectrum of Preterm Birth
G.C. Di Renzo, R. Luzietti, M. Mignosa, F. Taddei, G. Clerici and A. Cutuli
Centre of Perinatal and Reproductive Medicine, University of Perugia, Italy
Introduction and Epidemiology
Preterm birth is the leading cause of perinatal morbidity and mortality, usually affects 8 to 10
percent of births. Despite four decades of research, the rate of premature births has not changed.
Survival rates have increased and morbidity has decreased because of technologic advances in
perinatal and neonatal medicine.
The incidence of preterm births has been rather stable in the most countries, with few variations in
incidence.
Preterm birth has the tendency to recur within the same sibships. Once a woman has had one
preterm birth, her risk of a subsequent preterm birth is nearly four times higher.
Male fetuses have a 20% higher risk of being born preterm. Malformed fetuses tend to be born
preterm. Multiple pregnancy is associated with a two- to fivefold increased risk of preterm birth.
Etiology and Risk Factors
Many studies have investigated on preterm delivery for determining risk factors and high risk
populations.
In most cases, the causes of preterm labor is not diagnosed, and the etiology is likely to be
multifactorial. Preterm birth can potentially be prevented in less than one half of the mothers who
present in labor earlier than 37 weeks of gestation.
Risk factor for preterm labor are listed in table 1.
Women with a lower level of education and women belonging to the lower socio-economic classes
have a associated increase risk of having a preterm birth of about 50%. Cigarette smoking in
pregnancy is associated with an increased risk of same magnitude.
In a large case-control survey performed in Europe (17 countries) between 1995 and 1997, called
EUROPOP, the social differences of very preterm birth have been analysed. In this study 1675 very
preterm birth and 7965 at term birth have been included. The relationship between social factors
and very preterm birth was studied according to obstetric history and mode of delivery. Very
preterm birth was significantly related to low educational level among women with no previous
adverse pregnancy outcome and among primigravid women or those with previous first trimester
abortion.
Lumley in a review described a relative risk in preterm delivery of maternal, fetal and iatrogenic
factors. Diabetes mellitus, liver disease and nephritis are the maternal conditions with a higher
relative risk (RR) being 5.5, 4.1 and 4.8 respectively. Between the complications of pregnancy there
are: appendicitis (RR=2.8), low systolic/diastolic pressure (RR=2.5/3.1), hyperemesis (RR=4.1),
isoimmunization (RR=4.3), hemoglobin below 7 g/dl (RR=4.2), pre-eclampsia (RR=6.4), and
eclampsia (RR=5.8). Congenital uterine malformations are associated with a RR of 3.1, placental
abruption with 8.0 and placenta previa with 6.0.
Infections of the genitourinary tract are an important factor associated with preterm labor. Women
with Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Trichomonas vaginalis,
Gardnerella vaginalis have a higher rate of preterm births.
Risk assessment and Pathophysiology
A number of studies have attempted to identify biochemical (table 3) and clinical (table 4) markers
of preterm labor.
Risk scoring
Several demographic and socio-economic factors (previous preterm delivery, low socioeconomic
stauts, maternal age, multiple pregnancy, etc.) known to be associated with preterm labor have been
included in risk scoring. The sensitivity of this approach is poor and his applications failed to
reduce the incidence of preterm delivery.


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Uterine Contractions
The identification of an increased frequency of baseline uterine contractions has been proposed for
early recognition of the onset of preterm labor. Although the predictive value in some studies is
good, the time and the cost involved are unlikely at present to widespread application.
Cervical Assessment
Detection of cervical changes (shortening, softening, and progressive dilatation) by digital palpation
has been proposed to predict preterm labor.
More recently have been used vaginal ultrasound to appreciate cervical changes. For Iams et al., a
cervical canal shorter than 30 mm has a sensitivity and negative predictive value of 100% and a
specificity and positive predictive value of 55% for delivery in a group of women with a symptoms
of preterm labor (table 2).
Cytokines
An increased concentrations in the cervical and vaginal secretion of interleukin-6 and tumor-
necrosis factor is expression of production by the deciduas and fetal membranes following to
infections in women who could go to preterm delivery.
Corticotropin-releasing Hormone
Higher level of this hormone have been detected in women who subsequently went into preterm
labor but without intra-amniotic infection.
Clinical and experimental findings support the concept that most cases of preterm delivery reflect
four pathogenetic processes, which have a common final pathway leading to uterine contractions
and cervical modifications.
These processes are: 1) activation of the maternal or fetal hypothalamic-pituitary-adrenal (HPA)
axis (caused by stress or early onset of parturition); 2) decidual-chorioamnionitic or systemic
inflammation (caused by ascending genitourinary tract or systemic infection); 3) decidual
hemorrhage (caused by coagulopathy, hypertension, smoking, cocaine use and vascular lesions); 4)
pathologic distension of the uterus (due to polyhydramnios, multifetal pregnancy or uterine
anomaly).
1) Markers of maternal-fetal activation of HPA axis are: maternal psychosocial and
physiological indicators of stress (unmarried and poor mothers, major stressuful events); biological
markers of initiation of labor (plasma estriol, IGF-1 binding protein, hCG and CRH and/or
uteroplacental vascular dysfunction (uterine artery Doppler flow).
2) Markers of decidual-chorioamnionitic or systemic inflammation are: plasma and/or cervico-
vaginal IL-6 and IL-8, GSF-1, Fas ligand, vaginal pH, cervico-vaginal sialidases and mucinases and
other evidence of bacterial vaginosis or colonization with others microorganisms, C reactive
protein. Vaginal pathogens including N. gonorrhea, C. trachomatis, T. vaginalis, and bacterioides.
Particularly striking is the association between bacterial vaginosis and preterm delivery. Antibiotic
treatment of bacterial vaginosis reduces the rate of PTD (49% vs 31%) in high risk patients.
3) Markers of decidual hemorrhage are: vaginal occult blood, plasma immunoreactive tissue
factor and plasma thrombin-antithrombin III complexes. Decidual hemorrhage is associated with 3-
fold increase risk of preterm delivery. Seems that any cause of decidual haemorrhage is associated
with either intrinsic or extrinsic damage to the uterine spiral arteries.
4) Markers of pathologic uterine distension are: sonographic assessment of fetal number and
amniotic fluid index, history of M     llerian duct anomalies. The mechanism accounting for this
correlation appears to involve the transduction of a signal initiated by mechanical stretch of uterine
myometrial, cervical and fetal membrane cells through the cellular cytoskeleton to activate cellular
protein kinase.
Finally, markers of the final common pathway leading to membrane and/or cervical
extracellular matrix degradation and myometrial activation are: matrix metalloproteinases
MMP-1 and MMP-9, fetal fibronectin and sonographic evidence of cervical shortening and
funnelling. Several studies suggest that in presence of fetal fibronectin in cervico-vaginal secretions
between 24 and 36 weeks gestation is a sensitive and specific predictor of preterm delivery (table
5).
Conclusion
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For the future the better approach to identify at risk asymptomatic patients may be combining the
most useful biophysical and biochemical markers of such pathogenetic processes and also assess
underlying pathogenetic processes in order to facilitate targeted therapy. Further studies are needed
to assess the ability of these combined makers to identify asymptomatic patients and to assess the
relative contribution of each of four pathogentic processes to preterm delivery risk.
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Table 1

Table 2

Table 3

Table 4

Table 5




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