New research from the University of Birmingham, England, in collaboration with the World Health Organization, shows that tocolytic drugs used to delay preterm birth, and thus avert the ensuing associated mortality and morbidity, are all “probably effective in delaying preterm birth compared with placebo or no treatment.”
Expanded use of the drugs would be a safe means to reduce the global burden of neonatal death, the researchers suggest. Coauthor Victoria Hodgetts Morton, BMedSci, NIHR clinical lecturer in obstetrics at the University of Birmingham, said: “Preterm birth is the most common reason why a newborn baby may die, and the leading cause of death in children under 5 years of age.
“Tocolytics aim to delay preterm birth and allow time for the women to receive medicines that can help with baby’s breathing and feeding if born preterm, and medicines that lower the chance of cerebral palsy of the infant. Crucially, a short delay in preterm birth can enable women to reach specialist care.”
Network meta‐analysis drew on 122 trials
The new paper, published in Cochrane Reviews, aimed to find out which tocolytic was most effective in delaying preterm birth, safest, and with the fewest side effects. Researchers brought together data from 122 randomized clinical trials in a network meta‐analysis.
Unlike conventional Cochrane Reviews, this type of review simultaneously pools all direct and indirect evidence into one single coherent analysis. Indirect evidence is obtained by inferring the relative effectiveness of two competing drugs through a common comparator, even when these two drugs have not been directly compared. The method also enables researchers to calculate the probability for each competing drug to constitute the most effective drug with the least side effects. This thereby allowed the researchers to rank the available tocolytic drugs.
The trials, published between 1966 and 2021, involved 13,697 women across 39 countries and included high, middle and low-income states. The researchers looked for trials involving women with live fetus(es) who presented with signs and symptoms of preterm labor, defined as uterine activity with or without ruptured membranes; or ruptured membranes, with or without cervical dilatation or shortening or biomarkers consistent with a high risk of preterm birth.
Trials were eligible if they involved tocolytic drugs of any dosage, route, or regimen for delaying preterm birth, and compared them with other tocolytic drugs, placebo, or no treatment.
The team reported that overall, the evidence varied widely in quality, and their confidence in the effect estimates ranged from very low to high. Only 25 of the 122 studies (20%) were judged to be at “low risk of bias.” The effectiveness of different drugs was less clear in some of the studies considered.
Compared with the use of placebo or no tocolytic treatment, “all tocolytic drug classes assessed and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days,” the researchers found. “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 tocolytics.”
Their figures showed:
- Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio [RR] 1.12), and 7 days (RR 1.14).
- Calcium channel blockers (for example, nifedipine) may be effective in delaying preterm birth by 48 hours (RR 1.16), and probably effective in delaying preterm birth by 7 days (RR 1.15), and prolong pregnancy by a mean of 5 days (0.1 to 9.2).
- Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12).
- Oxytocin receptor antagonists (e.g., atosiban) are effective in delaying preterm birth by 7 days (RR 1.18), are probably effective in delaying preterm birth by 48 hours (RR 1.13), and possibly prolong pregnancy by an average of 10 days (95% confidence interval, 2.3 to 16.7).
- Nitric oxide donors (e.g., glyceryl trinitrate) are probably effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.18).
- Cyclooxygenase-2 inhibitors (e.g., indomethacin) may be effective in delaying preterm birth by 48 hours (RR 1.11).
- Combination tocolytics – most common was magnesium sulphate with betamimetics - are probably effective effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.19).
Uncertain mortality outcomes and a wide range of adverse effects
However, the effects of tocolytic use on neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection, were “uncertain,” the researchers said, and the drugs proved compatible with a wide range of effects compared with placebo or no tocolytic treatment for these outcomes.
“All tocolytics were compatible with a wide range of serious adverse effects (trials including 6,983 women) when compared with placebo or no treatment,” the researchers said. Betamimetics and combination tocolytics had the most side effects and were most likely to lead to cessation of treatment (results from 8,122 women).
Overall, “the findings show that the benefits of these drugs outweigh any risks associated with unwanted side effects,” said first author Amie Wilson, PhD, research fellow in global maternal health at the University of Birmingham. “These treatments are leading to a significant reduction in the number of deadly preterm births, and we now need to further understand the effectiveness of tocolytics for specific groups depending on pregnancy length,” she said.
“Our previous research has led to the improvement of guidelines for use of tocolysis drug use to delay preterm birth in the U.K. Knowing that this paper helped to inform the forthcoming recommendations of the World Health Organisation on the use of tocolytics, we hope that many more women around the globe will have access to these drugs, and have healthier births.”
A version of this article first appeared on Medscape UK.