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Objectives To describe the management of threatened preterm delivery (TPD) in France 3 years after publication of the French guidelines and to analyse the factors of variation of the practices observed. Design Population-based study. Setting Representative sample of French maternity units. The study included 107 hospitals, accounting for 20% of all French maternity units. Population Women hospitalised for TPD during May 2005. Methods Cross-sectional national practice survey. Results Of the 734 admissions for TPD, 12.1% involved premature rupture of membranes and 12.9% were in utero transfers. Women admitted for TPD accounted for roughly 6% of all annual deliveries, regardless of the unit’s level of care, and 42.4% of these women delivered preterm: none delivered before 32 weeks in level 1 maternity units, 11.6% in level 2 and 88.4% in level 3. Transvaginal cervical ultrasound was performed for 54.5% of the women with intact membranes. Tocolysis was administered in 87.1% of women with intact membranes, with 45.6% of such women receiving this intervention for longer than 48 hours. First-line tocolytics used were calcium channel blockers (53.7%), beta-agonists (34.7%) or atosiban (8.8%), but their distribution differed substantially according to level of care. Maintenance tocolysis was administered to 385 women (59.8%) with intact membranes. Of the women admitted before 34 weeks, 21.1% did not receive corticosteroids. Conclusions Practices for the management of TPD vary widely and appear to depend on the level of care. Some practices appear less than optimal, especially those related to duration of tocolysis, maintenance tocolysis, antenatal corticosteroid and use of cervical ultrasound.

Preterm birth remains one of the serious problems in perinatal medicine and is associated with an increased risk of neonatal complications and long-term morbidity. Although each day that delivery is delayed between 22 and 28 weeks of gestation increases survival by 3%, since most spontaneous preterm labour occurs between 28 and 34 weeks of gestation, this is of secondary concern; the primary goal of delay is to improve the function of certain systems in the fetus and to balance the risks of a hostile intrauterine environment with the complications of extrauterine preterm life. Although there is a lack of definitive evidence that tocolytic drugs improve outcome following spontaneous preterm labour and preterm birth, there is ample evidence that tocolysis delays delivery for long enough to permit administration of a complete course of antepartum glucocorticoids and to facilitate in utero transfer to a tertiary care unit where neonatal care will be optimal. Both these measures have been associated with improved outcomes; antepartum glucocorticoids reduce the incidence of respiratory distress syndrome, intraventricular haemorrhage, periventricular leucomalacia and necrotising enterocolitis, and in utero transfer is associated with decreased morbidity and mortality and less hospital-based intervention compared with postnatal transportation. Consequently, women who are more likely to benefit from tocolysis are those at early gestational ages, those needing transfer to a hospital that can provide neonatal intensive care and those who have not yet received a full course of antepartum glucocorticosteroids. In these cases, delaying labour for at least 48 hours with drugs such as atosiban should be considered, since it offers clear advantages for the fetus.

Over the past 15 years, the use of beta-agonists has declined worldwide. Following the Royal College of Obstetricians and Gynaecologists guidelines in 2002, clinicians in the UK and beyond were faced with the dilemma of continuing to use beta-agonists, desist from using tocolytic therapy completely or choosing to change to atosiban or calcium channel blockers (CCBs). While grade A level 1 evidence exists to show that atosiban is significantly more efficacious than placebo and significantly safer than beta-agonists for the treatment of spontaneous preterm labour, the evidence for CCBs, such as nifedipine, is much less robust and no placebo-controlled trials have been performed. Published studies on nifedipine are largely investigator-led studies of small sample size, which lack sufficient power. As a result, most of the evidence has been based on meta-analyses of these studies, which look retrospectively at pooled data and are only as good as the quality of the studies included. In light of this, a tool was developed to produce a systematic review of studies on tocolytic effectiveness, which can and should be applied to all tocolytics and which considered both method- and topic-specific markers of quality. In the process of applying this tool to nifedipine, an extensive literature search identified 31 studies for a systematic review of the quality of nifedipine studies assessed by eight paired reviewers with wide experience in the subject of spontaneous preterm labour and preterm birth. Forty topic- and method-specific items of quality were assessed. The paucity of good quality studies of nifedipine used for the treatment of spontaneous preterm labour should be highlighted in meta-analyses or systematic reviews, which measure efficacy and should limit and influence the degree to which recommendations and guidelines are made on the basis of such studies.

The rationale for using tocolytics in preterm labour is to enable transfer of the mother to a tertiary centre and to prolong pregnancy sufficiently so that glucocorticoids can be administered to the mother. There is little question that these short term objectives can be achieved with contemporary tocolytics. Whether tocolytics can maintain pregnancy for sufficient periods to enable in utero maturation to occur remains an unresolved question. When a decision is made to use tocolytics, the clinician is faced with a multitude of choices with side effects, efficacy and ease of administration generally being the most important considerations. Placebo-controlled studies suggest that the beta-agonists, prostaglandin inhibitors and atosiban are effective in prolonging pregnancy for 24-48 hours. Of these three agents, atosiban has the best safety profile. There are no placebo-controlled studies with calcium channel blockers or nitric oxide donors. However, because of their ease of use and efficacy compared with the beta-agonists, calcium channel blockers are widely used. Calcium channel blockers appear to have a better safety profile than the beta-agonists, but there are still significant cardiovascular side effects associated with their use. Indomethacin, although proven to be efficacious, has a safety profile that limits its utility for other than short courses. Magnesium sulphate is the most commonly used tocolytic in the United States, despite a lack of evidence for its efficacy. Although magnesium sulphate appears to have a good safety profile, serious side effects have been reported with its use. The choice of tocolytics is commonly based on personal preference. Whichever tocolytic is chosen, the fundamental parturitional process is not reversed by contemporary treatment, rather a reduction in uterine response to a stimulant; thus, the expectations of tocolytic treatment need to be reconsidered.

Objective Inhibiting preterm labour at extremely early gestations. Design Observational study. Case reports. Setting Perinatal Centre Lund University Hospital, South Sweden. Population Twenty-five women (13 cases with intact membranes and 12 cases with ruptured) with threatened preterm labour and advanced cervical status before 26 completed weeks of gestation. Methods A combination of different drugs was used. Atosiban, an oxytocin antagonist, was the first line drug and was given as an infusion for several days as required. Supportive therapy was also given to most women with subcutaneous injections of the β-receptor agonist terbutaline (0.25 mg up to six times a day); sulindac, a prostaglandin synthetase inhibitor (200 mg one to two times a day up to a week); and broad-spectrum antibiotics (metronidazole and cefuroxime intravenously for three days and thereafter oral therapy). Main outcome measures Prolongation of pregnancy more than 48 hours or 7 days. Neonatal survival. Results Prolongation of pregnancy for more than 48 hours to enable administration of corticosteroid therapy was obtained in all but three cases. Eight women were delivered after more than a week from admission. Three neonates died at birth due to obstetric complication or sepsis. The other neonates had normal pH in cord or venous blood at birth. No severe side effects were recorded and in no case did the treatment have to be discontinued due to side effects. Conclusion The policy described here is not evidence based, relating only to clinical observations, and as such is of very limited value. However, it seems that with this combined approach to management, some days can be gained by achieving full effect of corticosteroid treatment and prolongation of the pregnancy, hopefully reducing time in the neonatal intensive care in these critical cases. No severe side effects were reported.

The perfect tocolytic agent, which is completely safe for both the mother and fetus and, which will inhibit uterine contractions and stop preterm labour in every case does not exist and the search continues. Recently, research into a new group of tocolytic agents (the oxytocic antagonists) has led to the introduction of a new licensed drug, atosiban. Since the early 1950s, modifications of the oxytocin molecule have resulted in many analogues and antagonists, though initially none emerged as potentially useful drugs. Further modifications resulted in full uterotonic antagonism in animal models before an analogue was found that inhibited vasopressin-stimulated uterine contractions in non-pregnant healthy women. In vitro and animal models suggested the molecule was fully antagonistic, although it was found to be only partially agonistic in women. Further developments led to two modified oxytocin molecules with higher receptor affinity for human myometrium, both of which lacked agonism in humans. The analogue, atosiban, was found to be more potent and so was chosen for clinical evaluation in dysmenorrhoea and preterm labour. The first clinical reports were open label, observational pilot studies. Randomised, double-blind, phase II placebo-controlled studies followed showing that atosiban was significantly more effective than placebo with very few side effects. Dose-response studies and phase III studies in which study or placebo groups could use alternative tocolytic agents also suggested that atosiban was an effective tocolytic agent with very few adverse events. The recent worldwide comparative study of atosiban versus different beta-agonists represents the largest and most strictly controlled study of tocolytics ever published. Atosiban was found to be at least as effective as the beta-agonists as a tocolytic agent, but significantly less likely to result in maternal cardiovascular side effects or the need to discontinue therapy as a result of unacceptable side effects.

Today's dogma states that tocolytics can be used to prolong pregnancy for just 48 hours, allowing corticosteroids to be administered and transportation of the mother to a tertiary care centre. Surveys have shown that up to 30% of practitioners use maintenance tocolysis. Theoretically, maintenance tocolysis should be able to improve neonatal outcome by avoiding preterm birth and allowing delivery in the community maternity hospital or even at home, minimising social difficulties created by long distances between the mother and/or her baby and the rest of the family. This should result in fewer neonatal intensive care unit admissions, less respiratory distress syndrome and fewer long-term neurological sequelae. Such an effect has never been proven, probably because we do not know which women benefit from treatment, which do not require treatment because they are not in labour and which babies would better be born because chorioamnionitis and other insults jeopardize intrauterine development. Most studies on long-term tocolysis have been performed with beta-agonists. No improvement has been shown. On the contrary, a trend towards fetal harm with an increased risk for periventricular leucomalacia exists. Results from studies of one tocolytic should not be generalised; one published study on maintenance therapy with atosiban showed prolonged uterine quiescence and prolonged gestation, but was too small to detect differences in neonatal outcome. In the future, we need larger studies, not only to detect whether long-term tocolysis with newer tocolytics (oral oxytocin antagonists, prostaglandin receptor blockers) results in better neonatal outcome, especially at the lower gestational ages but also to discover methods that allow us to identify those women who will benefit from treatment and those for whom prolongation of pregnancy may cause harm.

The incidence of spontaneous preterm labour and preterm birth has increased, and its management worldwide remains suboptimal. While considerable debate remains as to whether long-term maintenance tocolysis is appropriate after an episode of spontaneous preterm labour, many practitioners support its use. Several drugs have been used for maintenance tocolysis, but they differ in terms of safety and efficacy. Atosiban and nifedipine are preferable for maintenance tocolysis, as they have been shown to be as effective as ritodrine while being associated with fewer adverse effects. Nifedipine is not licensed for use as a tocolytic. An ideal tocolytic should be utero specific, with few fetomaternal and fetal adverse effects, and should significantly improve perinatal outcome. To warrant the use of maintenance therapy, larger trials in women at particular gestational age ranges may be needed, in which the primary endpoints are perinatal outcomes. The inclusion of cost-effectiveness analyses would also be of benefit.