Oral betamimetics for maintenance therapy after threatened preterm labour

Available evidence indicates that oral betamimetics as a maintenance therapy after an episode of threatened preterm labour does not reduce the rate of preterm birth.

RHL Commentary by Güngördük K

1. INTRODUCTION

The incidence of preterm birth in the developed world is between 7% and 12% (1). A small gradual increase in the incidence of preterm birth has been associated with assisted reproduction resulting in multiple pregnancy and an increased tendency towards obstetric intervention. Because preterm birth is the most common cause of perinatal morbidity and mortality in many countries, its prevention and treatment are a major focus of obstetric care.

The consequences of preterm birth occur with increased severity and frequency with earlier gestational age of the newborn. In addition to perinatal death in the very young fetus, common complications of preterm birth include respiratory distress syndrome, intraventricular haemorrhage, necrotizing enterocolitis, sepsis, neurological impairment, and seizures. Long-term morbidity associated with preterm delivery includes bronchopulmonary dysplasia and developmental abnormalities including cerebral palsy (2). This Cochrane (3) review evaluated the effects of oral betamimetic maintenance therapy for preventing preterm birth after threatened preterm labour.

2. METHODS OF THE REVIEW

Primary outcomes considered were: very preterm birth (less than 34 weeks gestation); low birth weight (less than 2500 grams); need for admission to the neonatal intensive care unit (NICU); perinatal mortality; serious neonatal or infant morbidity, defined as growth restriction (birth weight less than the third percentile); chronic lung disease; seizures; birth asphyxia as defined by the trial authors; neonatal encephalopathy; disability in childhood); maternal death or serious maternal morbidity (e.g. complications related to tocolytic medication); and hospital admission. The review authors chose appropriate outcomes and used the standard Cochrane Pregnancy and Childbirth Review Group search strategy. Their assessment of the methodological quality and methods of data analyses of trials were appropriate.

3. RESULTS OF THE REVIEW

Based on predefined selection criteria, 13 trials with a total of 1551 women were included in the review.

3.1. Maintenance therapy with a betamimetic versus placebo or no treatment

Eight studies with a total of 1681 women comparing maintenance therapy with a betamimetic versus placebo or no treatment were considered for this analysis. The review authors found no differences for very preterm birth [one trial comparing ritodrine with placebo; risk ratio (RR) 2.81, 95% confidence interval (CI) 0.30–26.22, 120 women], low birth weight (one trial comparing ritodrine with placebo; RR 0.15, 95% CI 0.02–1.25, 140 women), admission to neonatal intensive care unit (one trial comparing terbutaline with placebo; RR 1.28, 95% CI 0.68–2.41, 260 women), or perinatal mortality (three trials comparing ritodrine with no treatment and three trials comparing terbutaline with no treatment; RR 2.41, 95% CI 0.86–6.74, 681 infants overall). No results with respect to maternal death or serious maternal morbidity were reported.

3.2. Maintenance therapy with a betamimetic (terbutaline) versus a prostaglandin synthesis inhibitor (indomethacin)

One study with 65 pregnant women following threatened preterm labour was included. The review authors reported no significant differences in very preterm birth (<34 weeks) between terbutaline and indomethacin (RR 0.64, 95% CI 0.24–1.76). Moreover, the authors found no differences in preterm birth within one week (RR 0.26, 95% CI 0.03–2.18).

3.3. Maintenance therapy comparing two betamimetics (terbutaline versus ritodrine)

One study with 91 pregnant women following threatened preterm labour was included. The review authors reported no significant differences in very preterm birth (<34 weeks) between terbutaline and ritodrine (RR 0.29, 95% CI 0.01–6.86).

3.4. Maintenance therapy with a betamimetic versus magnesium

Three studies with 383 pregnant women with threatened preterm labour were included. Two of these had used the betamimetic terbutaline, and one had used ritodrine. In one randomized controlled trial (RCT), no difference was found in admissions to neonatal intensive care unit when terbutaline was compared with magnesium (RR 0.80, 95% CI 0.43–1.46, 137 women, adjusted for twin gestations). In another trial that had compared ritodrine with magnesium, no significant difference in perinatal mortality was found (RR 0.20, 95% CI 0.01–3.97, 50 infants).

3. 5. Summary of the results

The review authors found no differences in admission to neonatal intensive care unit when betamimetics were compared with placebo (RR 1.28, 95% CI 0.68–2.41; two trials of terbutaline with 2600 women) or with magnesium (RR 0.80, 95% CI 0.43–1.46; one trial with 137 women). The incidence of preterm birth (<37 weeks) was not significantly different in six trials, four comparing ritodrine with placebo/no treatment and two comparing terbutaline with placebo/no treatment (RR 1.11, 95% CI 0.91–1.35, 644 women).

The authors also observed no differences between betamimetics and placebo, no treatment, or other tocolytics for perinatal mortality and morbidity, such as respiratory distress syndrome (RR 1.10, 95% CI 0.61–1.98, six trials), necrotizing enterocolitis (RR 0.98, 95% CI 0.22–4.28, two trials), intraventricular haemorrhage (RR 0.97, 95% CI 0.27–3.58, three trials), and neonatal jaundice (RR 1.67, 95% CI 0.71–3.89, one trial). Additionally, some adverse effects such as tachycardia were more frequent in the betamimetics groups than in the groups allocated to placebo, no treatment, or another type of tocolytic.

4. DISCUSSION

4.1. Applicability of the results

Sufficient available evidence indicates that oral betamimetics as maintenance therapy after an episode of threatened preterm labour does not reduce the rate of preterm birth. Although most trials included in the review were conducted in developed countries, there are no biological reasons to expect different results in developing countries. Therefore, the results are generalizable to developing countries.

4.2. Implementation of the intervention

Increased understanding of the pathophysiology of preterm labour over the past two decades has enabled us to change our approach to this problem, with increased focus on preventive strategies. There are three levels of prevention: primary, secondary, and tertiary. Primary prevention is the strategy directed at all women before or during pregnancy to prevent and reduce the risk of preterm birth. Primary interventions are beneficial to the overall health of the woman, as they include weight optimization, nutritional supplementation, smoking cessation, and the avoidance of late-preterm births. Secondary prevention efforts, which include cervical cerclage, progesterone, and antibiotic prophylaxis, are directed at women who are already at higher risk of preterm birth. Tertiary prevention is treatment after a diagnosis of preterm labour has been made in symptomatic women (4).

Tocolysis is usually used for ≤48 hours to allow a steroid effect. Betamimetics decrease the number of women in preterm labour giving birth within 48 hours compared with placebo and decrease the number of births within 7 days. However, oral betamimetic therapy for maintenance tocolysis does not prevent preterm labour, recurrent hospitalizations, or perinatal morbidity and mortality compared with placebo or other drugs. Some adverse effects such as tachycardia are more frequent in women treated with betamimetics as maintenance therapy. Given this ample evidence from 13 trials, there is absolutely no evidence to support the use of oral betamimetics after preterm labour has resolved.

4.3. Implications for research

Researchers who believe that oral betamimetics might be an effective maintenance therapy should conduct further well-designed randomized controlled trials. Any future trials should include the following: very preterm birth (less than 34 weeks' gestation); low birth weight (less than 2500 grams); neonatal mortality or serious neonatal or infant morbidity; and maternal death or serious maternal morbidity. Future research should also focus on the pathophysiological pathways that precede preterm labour.

References

  • Andrews, W. W., Goldenberg, R. L., Mercer, B. et al. The Preterm Prediction Study: association of second-trimester genitourinary chlamydia infection with subsequent spontaneous preterm birth. American Journal of Obstetrics and Gynecology 2000a;183, 662–628.
  • Doyle, L. W. and Casalaz, D. Victorian Infant Collaborative Study Group. Outcome at 14 years of extremely low birthweight infants: a regional study. Archives of Disease in Childhood Fetal Neonatalology 2001;85,159–64.
  • Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database of Systematic Reviews 2006;Issue 1. Art. No.: CD003927; DOI: 10.1002/14651858.CD003927.pub2.
  • Berghella V. Prevention of preterm birth. In: Berghella V Ed. Obstetrics; evidence based guidelines 2007. London: Informa Healthcare Ltd.; 2007.

This document should be cited as: Güngördük K. Oral betamimetics for maintenance therapy after threatened preterm labour: RHL commentary (last revised: 1 January 2013). The WHO Reproductive Health Library; Geneva: World Health Organization.

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