Abstract: Twelve trials involving 1586 women met inclusion criteria for this review. One trial did not report on the outcomes of interest in this review. Risk of bias of included studies: The included studies generally were of low quality based on inadequate reporting of methodology. Only three trials had low risk of bias for random sequence generation and one had low risk of bias for allocation concealment and participant blinding. Most studies were either high risk of bias or uncertain in these key areas. Comparison 1: Ethanol versus placebo/control (two trials, 77 women) Compared to controls receiving pain medications and dextrose solution, ethanol did not improve any of the primary outcomes: birth < 48 hours after trial entry (one trial, 35 women; risk ratio (RR) 0.93, 95% confidence interval (CI) 0.43 to 2.00), or neonatal mortality (one trial, 35 women; RR 1.06, 95% CI 0.31 to 3.58). Serious maternal adverse events and perinatal mortality were not reported by either of the two trials in this comparison. Maternal adverse events (overall) were not reported but one trial (42 women) reported that there were no maternal adverse events that required stopping or changing drug) in either group. One trial did report delay until delivery but this outcome was reported as a median with no mention of the standard deviation (median 19 days in ethanol group versus "less than 1" day in the glucose/water group). There were no differences in any secondary outcomes reported: preterm birth < 34 weeks or < 37 weeks; serious infant outcome; fetal alcohol syndrome/fetal alcohol spectrum disorder; or small-for-gestational age. Comparison 2: Ethanol versus other tocolytic (betamimetics) (nine trials, 1438 women) Compared to betamimetics (the only tocolytic used as a comparator in these studies), ethanol was associated with no clear difference in the rate of birth < 48 hours after trial entry (two trials, 130 women; average RR 1.12, 95% CI 0.53 to 2.37, Tau² = 0.19, I² = 59%), similar rates of perinatal mortality (six trials, 698 women; RR1.20, 95% CI 0.78 to 1.84), higher rates of neonatal mortality (eight trials, 1238 women; RR 1.43, 95% CI 1.02 to 2.02), higher rates of preterm birth < 34 weeks (two trials, 599 women; RR 1.56, 95% CI 1.11 to 2.19), higher rates of neonatal respiratory distress syndrome (three trials, 823 women; RR 1.76, 95% CI 1.33 to 2.33), and higher rates of low birthweight babies < 2500 g (five trials, 834 women; RR 1.30, 95% CI 1.09 to 1.54). These outcomes are likely all related to the lower incidence of preterm birth seen with other tocolytics, which for all these comparisons were betamimetics. Serious maternal adverse events were not reported in any of the nine trial reports. However, ethanol had a trend towards a lower rate of maternal adverse events requiring stopping or changing the drug (three trials, 214 women; RR 0.25, 95% CI 0.06 to 0.97). There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Planned sensitivity analysis, excluding quasi-randomized trials did not substantially change the results of the primary outcome analyses with the exception of neonatal mortality which no longer showed a clear difference between the ethanol and other tocolytic groups (3 trials, 330 women; RR 1.49, 95% CI 0.82 to 2.72). This review is based on evidence from twelve studies which were mostly low quality. There is no evidence that to suggest that ethanol is an effective tocolytic compared to placebo. There is some evidence that ethanol may be better tolerated than other tocolytics (in this case betamimetics), but this result is based on few studies and small sample size and therefore should be interpreted with caution. Ethanol appears to be inferior to betamimetics for preventing preterm birth in threatened preterm labor. Ethanol is generally no longer used in current practice due to safety concerns for the mother and her baby. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth in threatened preterm labour. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.

Plain-language summary: We searched for trials evidence on 31 May 2015 and found 12 trials total involving 1586 women, some comparing ethanol with a placebo and others comparing ethanol with other tocolytics (in this instance, all betamimetics). The trials included in this review were considered to be mostly low quality studies. For our comparison of ethanol versus placebo control (two trials, 77 women). We found that ethanol was no better than placebo (sugar water) for any of the outcomes studied: birth <48 hours after trial entry (one trial, 35 women) or neonatal mortality (one trial, 35 women). Serious maternal adverse events and perinatal mortality was not reported. There was no differences between groups for other outcomes: preterm birth < 37 weeks or < 34 weeks, serious infant outcome, fetal alcohol syndrome/fetal alcohol spectrum disorder, or small-for-gestational age. We also compared ethanol with other tocolytic drugs (nine trials involving 1438 women; all trials studied betamimetic drugs). We found that ethanol was worse than other betamimetic drugs at postponing birth until after 34 weeks' gestation and led to a higher rate of low birthweight babies, babies with breathing problems at birth and neonatal death (although there was no clear difference in neonatal deaths when we restricted our analyses to the better quality studies), However, we did find that, compared to betamimetics, ethanol was associated with a trend for fewer maternal side effects that required stopping or changing the drug, though this result is based on three small trials. There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Overall, we found no evidence that ethanol was better than a placebo at postponing preterm labor and birth. Whilst there was some evidence to suggest that ethanol may be better tolerated than betamimetics, we found that ethanol was not as effective as betamimetics at postponing preterm labor and birth. None of the studies were long-term ones and thus none of them reported on the risk of giving ethanol on the babies developing fetal alcohol syndrome, which can cause mental retardation. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.