Atosiban – A Specific Evolution for the Management of Preterm Labour

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Why Treat Preterm Labour?

Preterm labour remains the leading cause of neonatal mortality and morbidity. The current Epicure study in the UK suggests that almost 50% of babies born at 23-25 weeks gestation will have significant long term handicap. At the very least, delaying delivery for 48 hours can allow antenatal steroid treatment which reduces the incidence of neonatal respiratory distress syndrome and mortality.

Who to Treat for Preterm Labour

Risk factors. The presence of ‘risk factors’ in the woman’s history could theoretically be used to select a group of women for treatment.. Probably the most efficient risk factor known is a previous preterm birth, which is associated with about a three-fold increase in the risk of a further preterm delivery1. However, this only raises the risk to about 30% and is not applicable to nulliparae. In women in their first pregnancies, a low body mass index is one of the better predictors1,2 but the relative risk is only about 2 in women with spontaneous ovulation (the preterm delivery rate is up to 50% in underweight women who require ovulation induction to conceive2, but this is a very small group). Other risk factors such as minority ethnic origin, poor socio-economic status, and working during pregnancy have a significant association with preterm labour, but the relative risk is only about 1.5. There have been many attempts to combine the various risk factors into a ‘risk score’, but they fail to identify even half the women who actually deliver preterm. Predictive techniques. In continental Europe, regular digital cervical examination has been a popular approach to detecting women at high risk of preterm labour. However, a recent prospective randomised trial of 5602 women failed to show either an increase in applied interventions to prevent preterm labour, or a reduction in the preterm delivery rate3. Ultrasound examination of the cervix has suggested that with cervical lengths less than the 10% percentile (2.5cm) at 24 and 28 weeks, the relative risk of preterm birth is increased4. The presence of funnelling, which was 5.9% and 8.6% at 24 and 28 weeks respectively, was also a risk factor for preterm birth. Active measures to produce ‘funnelling’ as a test of cervical competence have also been described5; 5; 6; however, evidence of the value of the technique is currently weak. Monitoring of uterine activity, for example with home tocographs, has not proved to be efficacious7-11. The finding of fetal fibronectin in vaginal secretions is associated with a substantial risk of preterm labour12-17. However, even sampling at regular two weekly intervals was found in some studies to be too non-specific for reliable prediction18. Fibronectin screening alone has yet to be shown to have any impact on the preterm delivery rate, perhaps because of the perennial problem, lack of an effective intervention19. Currently, screening for bacterial vaginosis is undergoing a similar evaluation20-22.

Diagnosis. This remains difficult. Progressive dilatation of the cervix is probably the only conclusive proof of labour, even demonstration of amniotic fluid draining per vaginam is not associated with progressive labour in about 20% of cases. Keirse and colleagues’ meta-analysis of 16 trials of betamimetics in ‘preterm labour’23 showed that in the untreated group, 412 of 660 (62%) did not deliver within 48 hours and 249 of 720 women (34.5%) did not deliver until term. Thus, any treatment given when preterm labour is diagnosed is likely to be unnecessary in about half the cases. In any case, in many preterm labours, tocolysis is inappropriate. In Tucker et al’s study of 13,119 singleton births24, there were 1445 preterm births (11%) but 630 (44%) of these were greater than 34 weeks gestation and treatment was therefore not indicated. 241 women had preterm premature rupture of membranes, and tocolysis was deemed inappropriate because of the risk of infection. In 238 women, birth was appropriate (26% had raised blood pressure, 22% had an intrauterine death, 16% had intrauterine growth retardation and 189 were 3cm or more dilated). Only in 147 was tocolysis possible, i.e. 5% of the 815 babies < 35 weeks, or just about 1% of total births.

Current tocolytic therapy. Older tocolytics such as alcohol and isoxuprine hydrochloride have now been abandoned as largely ineffective and with too many side effects. All currently used tocolytics also have important side effects. The risks of tocolysis with b agonists include fluid overload and pulmonary oedema, myocardial ischaemia, hyperglycaemia, hypokalaemia and death25-35. With indomethacin, the risks are both maternal (peptic ul ceration, gastrointestinal bleeding, thrombocytopaenia, and allergic reactions) and fetal (pulmonary hypertension secondary to premature closure of the ductus arteriosus, persistent non-closure of the ductus post-delivery with resistance to further indomethacin therapy, necrotising enterocolitis and small bowel perforation, periventricular and intraventricular haemorrhage, an increase in respiratory distress syndrome and bronchopulmonary dysplasia, and impaired renal function36-47). In the USA, magnesium sulphate is widely used and this can cause adult respiratory distress syndrome, respiratory depression, hypothermia, paralytic ileus and cardiac arrest, and osteoporosis as well as fetal bradycardia and loss of heart rate variability48-51. It also has a low therapeutic ratio (low ratio between effective and toxic effect52), and may increase neonatal mortality53. Calcium channel blockers are also used for tocolysis, but an obvious side-effect is that they cause significant hypotension. Their maternal side-effect profile is better than beta sympathomimetics54 but effects on the fetus have caused concern55; 56. It has been suggested that sublingual nifedipine should be removed from the market57. Of particular concern is the interaction of calcium channel blockers with magnesium sulphate, being reported as causing respiratory failure58; 59, colonic pseudo-obstruction60, and severe vulval oedema61.

Need for a new tocolytic. It is evident from the above that an effective tocolytic that had few or no side-effects would be extremely valuable.

References:

Reference List

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60. Pecha RE, Danilewitz MD. Acute pseudo-obstruction of the colon (Ogilvie’s syndrome) resulting from combination tocolytic therapy. Am J Gastroenterol 1996;91:1265-1266.

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