Abstract: We included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data. All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies. There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies. Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events. This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results. There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone). There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions. Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling.

Plain-language summary: We searched the medical literature widely for randomised controlled trials that investigated the effects of progesterone in people with TBI up to 30 September 2016. Randomised controlled trials provide the most robust medical evidence. . We included five studies with a total of 2392 participants, and identified three ongoing studies. The studies all compared a group of participants who received progesterone within 24 hours of TBI against a group who received a pretend - or dummy - medicine (known as a placebo) that looked the same as the progesterone. The results of our review did not find evidence that, when compared to placebo, progesterone could reduce death and disability in people with TBI. There were too few data available on the other outcomes that we were interested in (pressure inside the skull (intracranial pressure), blood pressure, body temperature and adverse events (harms)), for us to be able to analyse these in detail. However, although the information available shows no evidence of a difference in effect between the progesterone and control groups for intracranial pressure, blood pressure or body temperature, one study showed an increased level of an adverse event called phlebitis (inflammation in the vein) in the progesterone group, possibly because the progestreone was given into the vein through an intravascular infusion ('drip'). We judged the quality of the evidence to be low for the data on risk of death, and moderate for the data on risk of disability. These judgements resulted from differences across studies, including different doses of progesterone and different time points for assessment of participants in the included studies. This means that we have limited confidence in the conclusions of this review.