Key messages
• All tocolytics (medicines that delay labour) that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours and for 7 days compared with placebo (a dummy treatment) or no tocolytic treatment,
• Tocolytics cause a wide range of unwanted effects (from minor to potentially severe) compared with placebo or no tocolytic treatment. Women taking betamimetics and combinations of tocolytics were more likely to stop taking them as a result of unwanted effects.
• The effects of tocolytics on deaths of babies before and after birth, and on infection in mothers and babies were uncertain.
What is the issue?
Preterm birth is the most common reason why a newborn baby may die, and is the leading cause of death in children under five years of age. Preterm birth (previously called premature birth) is defined as birth of a baby before 37 completed weeks of pregnancy. The earlier the baby is born, the poorer the outcome. Preterm infants are not only at increased risk of death, but also serious illness. They are more likely to face breathing complications, difficulties with feeding and body temperature regulation. Long-term complications include disability associated with brain function, and lung and gut complications.
Why is this important?
Tocolytics aim to delay preterm birth and allow time for women to receive medicines that can help with baby's breathing and feeding if born preterm, and medicines that lower the chance of the infant having cerebral palsy. Crucially, a short delay in preterm birth can enable women to reach specialist care. The aim of this Cochrane Review was to find out which tocolytic is most effective in delaying preterm birth, and has the fewest unwanted effects. We collected and analysed all studies to answer this question (date of search: 21 April 2021)
What evidence did we find?
We searched for evidence and identified 122 studies of 13,697 women involving six classes of tocolytics (betamimetics, COX inhibitors, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, and nitric oxide donors), combinations of tocolytics, and placebo or no tocolytic treatment. Of 122 studies, we judged 25 (20%) to provide the most trustworthy evidence. Overall, the evidence varied widely in quality, and our confidence in our results ranged from very low to high. We compared the different tocolytics against each other as well as against placebo or no treatment.
Delay in birth by 48 hours and 7 days
• Betamimetics may be effective in delaying preterm birth by 48 hours (9853 women), and 7 days (7143 women).
• Calcium channel blockers may be effective in delaying preterm birth by 48 hours, and probably effective in delaying preterm birth by 7 days.
• Magnesium sulphate might be effective in delaying preterm birth by 48 hours.
• Oxytocin receptor antagonists are effective in delaying preterm birth by 7 days, might be effective in delaying birth by 48 hours and possibly result in pregnancy prolongation in average of 10 days (5093 women).
• Nitric oxide donors might be effective in delaying preterm birth by 48 hours, and 7 days.
• COX inhibitors may be effective in delaying preterm birth by 48 hours.
• Combinations of tocolytics - most commonly magnesium sulphate combined with betamimetics - might be effective in delaying preterm birth by 48 hours, and 7 days.
• The most effective tocolytics for delaying preterm birth by 48 hours, and 7 days were the nitric oxide donors, calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics.
Serious unwanted effects and ending treatment due to unwanted effects
• Tocolytics are associated with a wide range of serious unwanted effects (6983 women) compared with placebo or no treatment.
• Betamimetics and combinations of tocolytics caused the most unwanted effects leading most women to stop treatment.
• Tocolytics are associated with a wide range of treatment effects compared with placebo or no tocolytic treatment for neonatal death at 28 days (8395 babies) and maternal infection (1399 women); so their effects were uncertain.
Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.
Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.
To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.
We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.
We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.
At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.
This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied.
Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence).
Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics.
Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment.
Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence).
In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).