Tocolytics for preterm labour

Success in the management of preterm labour is very much related to the initiation of treatment as soon as possible and administration of corticosteroids for fetal lung maturity. Calcium channel blockers are preferred to other agents for stopping labour contractions

RHL Commentary by Özmen Ş

1. EVIDENCE SUMMARY

This commentary covers two Cochrane reviews that focus on medical treatments to inhibit preterm labour.

One of them assesses the effects of calcium channel blockers on maternal, fetal and neonatal outcomes when administered as a tocolytic agent to women during preterm labour. It makes two comparisons: (i) calcium channel blockers versus placebo or no intervention; and (ii) the effects of any dihydropiridine class calcium channel blockers (e.g. nifedipine and nicardipine) versus any betamimetic agent. Twelve randomized controlled trials involving 1029 women are included in the review, with nine of them (817 women) being evaluated in the subgroup analysis for comparison of dihydropiridine class of calcium channel blockers versus any betamimetic agent.

The use of calcium channel blockers, when compared with any other tocolytic agent, showed a statistically significant decrease in the number of women giving birth within seven days of initiation of the treatment (relative risk [RR] 0.76; 95% confidence interval [CI] 0.60–0.97). Outcomes such as pregnancy prolongation (weighted mean difference [WMD] 3.83 days; 95% CI 3.04-10.70), birth prior to 37 weeks gestation (RR 0.95; 95% CI 0.83-1.09) and birth within 48 hours of initiation of treatment (RR 0.80; 95% CI 0.61-1.05) favoured calcium channel blockers, although the latter two outcomes did not reach statistical significance. For every 11 women treated with a calcium channel blocker rather than another tocolytic one less can be expected to deliver within seven days (number needed to treat [NNT]= 11; 95% CI 6-100). Calcium channel blockers are associated with fewer maternal adverse drug reactions (RR 0.32; 95% CI 0.24-0.41) and cessation of treatment due to side-effects (RR 0.14; 95% CI 0.05-0.44).

The use of calcium channel blockers resulted in statistically and clinically significant benefits for the baby. Neonatal respiratory distress syndrome (RR 0.63; 95% 0.46-0.88) necrotising enterocolitis (RR 0.21; 95% 0.05-0.96), intraventricular haemorrhage (RR 0.59; 95% CI 0.36-0.98) and neonatal jaundice (RR 0.73; 95% CI 0.57-0.93) were all reduced. The risk reduction for the outcome of respiratory distress syndrome gives a NNT value of 14 (95% CI 8-50) and for intraventricular haemorrhage 13 (95% CI 7-100).

The second review evaluated the effects of oxytocin receptor antagonists (atosiban) for inhibiting preterm labour (1). Two trials compared atosiban with placebo and four trials compared atosiban with betamimetics. When compared with placebo, atosiban resulted in lower birth weight (WMD -138.31 gm; 95% CI – 248.76 to -27,86), an increase in infant death at 12 months of age (RR 6.15;95% CI 1.39–27.22) and an increase in maternal adverse drug reaction (RR 4.02; 95%CI 2.05 to 7.85). There were more women in earlier gestational ages in the atosiban group which could explain the increased number of infant deaths.

Compared with betamimetics more atosiban-exposed infants had birth-weights under 1500 gm (RR 1.96;95% CI 1.15–3.35), but neither neonatal mortality nor neonatal morbidity differed. Atosiban was associated with significantly less maternal drug reactions when compared with betamimetics (RR 0.04; 95% CI 0.02–0.11). Moreover, atosiban did not reduce the incidence of delivery before 48 hours after initiation of treatment, respiratory distress syndrome and admission to neonatal intensive care.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

The incidence of preterm birth is generally around 6–7% of all births (2). In the USA the incidence is 11.5% (3). In Europe, the incidence is 5.8%, and in Turkey it is 5.6% (4, 5). Despite numerous management protocols proposed, the incidence of preterm birth has changed little over the past 40 years (3). Preterm birth is the leading cause of neonatal mortality both in developed and developing countries (3, 6). Global estimates for 2001 suggest that 24% of neonatal deaths are due to complications of prematurity (7). Preterm labour is the most common cause for antenatal hospitalization in developed countries (8).

Since there are large variations in symptoms of preterm labour, and with routinely used clinical tools it is difficult to determine precisely a woman’s risk, the assessment of preterm delivery risk is often inaccurate (9). In 80% of women with presumptive preterm labour, preterm delivery will not occur (9). Besides the inaccuracy of the diagnosis, there is uncertainty about the best strategies for managing preterm labour. The most effective intervention to improve newborn outcomes for women in preterm labour is the administration of corticosteroids (10). A significant reduction in respiratory distress syndrome is obtained if delivery can be postponed for 48 hours. Pharmacological treatment of preterm labour should aim at preventing preterm delivery for at least 48 hours (10).

Although the perinatal mortality and morbidity associated with preterm birth decreases with increasing gestational age the burden on the health system of neonatal intensive care due to prematurity is substantial.

2.2. Applicability of results

In managing preterm labour clinicians have two immediate concerns: to be able to have enough time to administer corticosteroids in order to accelerate fetal lung maturity and to provide safe and timely maternal transport to a facility with a neonatal intensive care unit. Calcium channel blockers are able to prolong the pregnancy for 3.83 days (95% CI 3.04-10.70) on average. This delay could provide adequate time to administer corticosteroids and to transport the mother to a tertiary-level referral hospital.

Studies from different countries have found similar tocolytic efficacy (coupled with fewer maternal side-effects) with nifedipine (11). These studies support the fact that calcium channel blockers can be used in different settings with similar efficacy and side-effects.

In developing countries, neonatal intensive care units are usually found in tertiary-level referral hospitals, but not all such units have the required treatment capabilities. The statistically significant benefits of calcium channel blockers in reducing neonatal respiratory distress syndrome and neonatal jaundice are even more important in developing countries because of the limited capacities of the neonatal intensive care facilities. The potential benefits of effective tocolysis may be higher in low-income countries because of the shortage of neonatal intensive care facilities. Thus, calcium channel blockers should be considered as first-line tocolytic agents in these countries.

2.3 Implementation of the intervention

According to the evidence presented in the two reviews, calcium channel blockers should replace betamimetics as first-line tocolytic agents. However, betamimetics are the only agents licensed for tocolysis in preterm labour in many countries (5). Since calcium channel blockers are an established group of drugs that are indicated and licensed for hypertension treatment, it should be possible to get them registered also as tocolytic agents. Nifedipine has recently been included as an antioxytocic (section 22.2) in the WHO Model List of Essential Medicines (12).

Although oxytocin receptor antagonists have been developed specifically as tocolytics, there is no evidence of benefit for the infant compared with betamimetics or placebo. To date, trials comparing atosiban with calcium channel blockers have not been undertaken. Coomarasamy et al. reported an indirect comparison of atosiban and nifedipine and found that nifedipine was more effective than atosiban and lowered the incidence of respiratory distress syndrome (13).

Nifedipine has the advantages of being easily available, oral administration and is cheaper than betamimetics and oxytocin receptor antagonists. These advantages are especially important for under-resourced settings.

3. RESEARCH

Further research is needed in the following areas:

  • Further trials to test different dosage regimens and formulations (capsules versus tablets) should be conducted.
  • The use of calcium channel blockers in tocolysis maintenance needs further study.
  • In complicated cases of preterm labour, the use of calcium channel blockers in conjunction with other tocolytic drugs needs to be researched further.
  • The long-term effect of calcium channel blockers on the development of children needs to be investigated.
  • Well-designed trials are needed to compare calcium channel blockers with oxytocin antagonists.

References

  • Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour (Cochrane Review). In: The Cochrane Library, Issue 3, 2005. Chichester: John Wiley & Sons.
  • King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester: John Wiley & Sons.
  • Martin JA, Hamilton BE, Ventura SJ, Menacker F, Park MM, Sutton PD. Births: final data for 2001. National Statistics Report 2002;51(2):1-104.
  • Çalışkan E, Öztürk N, Aykan B, Yalvaç S, Dilbaz B, Haberal A. Analysis of 47145 deliveries in a tertiary centre: an epidemiological view. Gynecology obstetrics and reproductive medicine 2003;9:88-91.
  • Ingemarsson I, Lamont RF. An update on the controversies of tocolytic therapy for the prevention of preterm birth. Acta obstetricia et gynecologica Scandinavica 2003;82:1-9.
  • Abu-Rashid N, Al-Jirf S, Bashour H. Causes of death among Syrian children using verbal autopsy. Web site www.emro.who.int/Publications/EMHJ/0203/11.htm;visited on 17 January 2005.
  • Darmstadt GL, Lawn JE, Costello A. Advancing the state of the world's newborns. Bulletin of the World Health Organization 2003;81:224-225.
  • Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery: etiologic heterogeneity. American journal of obstetrics and gynecology 1991;164:467–471.
  • American College of Obstetrics and Gynecology Practice Bulletin. Management of preterm labour. Obstetrics and gynecology 2003;101:1039–1046.
  • Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software.
  • İvit H, Köksal A, Yavuzşen HT, Çukurova K, Keklik A, Yıldız A, Zeybek. Comparison of nifedipine and ritodrine for the treatment of preterm labour. Türkiye klinikleri jinekoloji ve obstetrik dergisi 2003;13:26–30.
  • WHO Model List of Essential Medicines, 14th edition. http://mednet3.who.int/EMLib/DiseaseTreatments/MedicineDetails.aspx?MedIDName=228@nifedipine (revised in March 2005) (accessed on 04 October 2005) .
  • Coomarasamy A, Knox EM, Gee H, Song F, Khan KS. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a metaanalysis with an indirect comparison of randomized trials. British Journal of Obstetrics and Gynaecology 2003;110:1045 –1049.

This document should be cited as: Özmen Ş. Tocolytics for preterm labour: RHL commentary (last revised: 27 January 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.

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