Tocolytics for delaying preterm birth: a network meta-analysis
Preterm birth is the most common reason why a newborn baby may die, and 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, lung and gut complications.
Tocolytics aim to delay preterm birth and allow time for the women to receive drugs that can help with baby's breathing and feeding if born preterm, and drugs that lower the chance of cerebral palsy of the infant. 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, safe and has the least side effects. We collected and analysed all studies to answer this question (date of search: 21 April 2021)
We searched for evidence and identified 122 studies of 13,697 women involving six classes of tocolytic drugs (betamimetics, COX inhibitors, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, and nitric oxide donors), combination of tocolytic drugs, and placebo or no treatment with a tocolytic. 25 of 122 studies (20%) were judged to be at ’low risk of bias’. Overall, the evidence varied widely in quality, and our confidence in the effect estimates ranged from very low to high. We compared the different drugs against each other as well as against placebo or no treatment. The evidence suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no treatment.
Betamimetics may be effective in delaying preterm birth by 48 hours (9,853 women), and 7 days (7,143 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 i 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 (5,093 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. Combination of tocolytics - most common is combination of magnesium sulphate 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 combination of tocolytics.
All tocolytics are compatible with a wide range of effects for serious adverse effects (6,983 women) when compared with placebo or no treatment, but betamimetics and combination of tocolytics had the most side effects leading to cessation of treatment (8,122 women). Tocolytics are compatible 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 (1,399 women); so their effects were uncertain.
Compared with the use of placebo or no tocolytic treatment, all tocolytic drug classes 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 wide range of side 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 and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.