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Correspondence: Professor K. Friese, Director of the Women's Hospital, University of Rostock, Doberaner Straße 142, 8057 Rostock, Germany.
Although there are many maternal characteristics associated with preterm birth, the aetiology in most cases is poorly understood. Our research demonstrates that multiple risk factors, such as maternal age and especially infection, are associated with preterm birth. Bacterial vaginosis and intrauterine infection are now believed to be an important risk factor for preterm delivery.
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Approximately 5–7% of all deliveries in Germany are preterm, yet, despite intense efforts, this situation has not improved over the last 15 years. With a birth rate of 800,000 per year in Germany, there are approximately 50,000 preterm newborns.
The outcome of extremely preterm infants has improved due to antepartum, intrapartum and neonatal intensive care. However, the incidence of preterm birth remains unchanged and assisted reproductive techniques continue to increase further the rate of preterm birth. The main problem is in prenatal care.
Cost of Preterm Birth
The costs are preterm birth are high. For example, the estimated costs per year based on data released by German hospitals is as follows:
• preterm delivery <32 weeks gestation 300 million Euros
• preterm delivery ≥32 weeks gestation 400 million Euros
• costs of tocolytic therapy 112 million Euros
The overall costs are more than 0.8 billion Euros a year. However, the costs of neonatal morbidity due to preterm delivery are not included. Therefore, the overall costs must be estimated to exceed 1 billion Euros per year.
There are several risk factors associated with preterm birth, such as bacterial vaginosis, smoking, previous preterm delivery and abortion. In 1995, Hillier et al.1 undertook a large study of the association between bacterial vaginosis and the preterm delivery of infants with low birthweight after accounting for other known risk factors. Bacterial vaginosis was detected in 16% of the 10,397 women. In a multivariate analysis, the presence of bacterial vaginosis was related to preterm delivery of a low-birth-weight infant (odds ratio (OR) 1.4). Other risk factors that were significantly associated with such a delivery in this population were the previous delivery of a low-birthweight infant (OR 6.2), the loss of an earlier pregnancy (OR 1.7), primigravidity (OR 1.6), smoking (OR 1.4) and abortion (OR 1.7).
Role of Infection
The role of infection is gaining importance in the aetiology of preterm birth. In 2000, Goldenberg et al.2, found that up to 80% of women who deliver before 30 weeks gestation have evidence of bacterial infection in the amniotic fluid and/or membranes compared with only 30% at ≥37 weeks gestation. Organisms frequently cultured following preterm delivery include Ureaplasma urealyticum, Mycoplasma hominus, Bacteroides species and Gardnerellavaginalis. When such organisms are found in the amniotic fluid of pregnant women prior to 20 weeks, the pregnancy usually ends 4 to 8 weeks later.
In Germany, research findings suggest that interleukin (IL)-6 and IL-6 receptors found in histopathology specimens from infants who died preterm show an association between intraventricular haemorrhage (IVH), periventricular leucomalacia and infection. We demonstrated that extremely immature preterm infants have a high expression of IL-6 and IL-6 receptors in the ganglionic eminence of the brain resulting in high protease activity and leading to vascular fragility and intracranial haemorrhage. Intrauterine infection at an early gestational age has been shown to be a strong predictor of IVH. Preterm neonates with histologically detected amnionitis have a 3–4 fold increased risk of developing IVH.
Overexpresion of the IL-6 receptor in the ganglionic eminience of the fetal brain between 22 and 28 weeks gestation compared with 32 to 36 weeks has been suggested as a possible reason3. Interleukin-6 supports the release of proteases, which contribute to IVH and periventricular haemorrhage and causes regression of the gangionic eminence. There are a number of markers that are strongly associated with intrauterine infection and these are summarised in Table 1. The complex relationship between infection, cytokines and preterm delivery is illustrated in Fig. 1.
Table 1. Parameters for intrauterine infections.
Cervix or vagina
Women in labour
↑ C-reactive protein
↑ Fetal fibronectin
Asymptomatic women in routine obstetrical care
↑ Fetal fibronectin
Prevention and Management Programme
As a result of the high preterm birth rate in Germany, our research group developed a management programme. Firstly, based on a national programme called ‘Baby care’, pregnant women were counselled with respect to special risks. The programme relied upon an information booklet and on a comprehensive questionnaire about past medical history, current pregnancy and lifestyle. The resulting data were examined using sophisticated computer software and a statement was sent back to the patients following which the patient discussed the proposals with her obstetrician.
Secondly, since up to 40% of preterm births are associated with infection; antenatal diagnostic surveillance was intensified using pH measurements to exclude bacterial vaginosis and if necessary to the use of early antibiotic therapy, such as metronidazole or clindamycin.
For imminent preterm labour, tocolysis with the oxytocin antagonist, atosiban, is used as first-line therapy. Other options include beta-agonists and magnesium sulphate infusion. For fetal lung maturation, betamethasone is administered for two doses (this is repeated in multiple pregnancy). Antibiotic prophylaxis with mezlocillin is adminstered for 3 days or following an antibiogram.
In summary, infection plays a significant role in spontaneous preterm labour and preterm birth and in the neonatal complications, which follow. A number of measures such as the identification of risk factors using patient history and lifestyle records together with antenatal diagnostic tests, such as pH measurements and screening for abnormal genital tract flora to diagnose early intrauterine infection, may help to predict and prevent the likelihood of preterm birth.