Risk of Adverse Outcomes in Females Taking Oral Creatine Monohydrate: A Systematic Review and Meta-Analysis

Abstract

Creatine Monohydrate (CrM) is a dietary supplement routinely used as an ergogenic aid for sport and training, and as a potential therapeutic aid to augment different disease processes. Despite its increased use in recent years, studies reporting potential adverse outcomes of CrM have been mostly derived from male or mixed sex populations. A systematic search was conducted, which included female participants on CrM, where adverse outcomes were reported, with meta-analysis performed where appropriate. Six hundred and fifty-six studies were identified where creatine supplementation was the primary intervention; fifty-eight were female only studies (9%). Twenty-nine studies monitored for adverse outcomes, with 951 participants. There were no deaths or serious adverse outcomes reported. There were no significant differences in total adverse events, (risk ratio (RR) 1.24 (95% CI 0.51, 2.98)), gastrointestinal events, (RR 1.09 (95% CI 0.53, 2.24)), or weight gain, (mean difference (MD) 1.24 kg pre-intervention, (95% CI -0.34, 2.82)) to 1.37 kg post-intervention (95% CI -0.50, 3.23)), in CrM supplemented females, when stratified by dosing regimen and subject to meta-analysis. No statistically significant difference was reported in measures of renal or hepatic function. In conclusion, mortality and serious adverse events are not associated with CrM supplementation in females. Nor does the use of creatine supplementation increase the risk of total adverse outcomes, weight gain or renal and hepatic complications in females. However, all future studies of creatine supplementation in females should consider surveillance and comprehensive reporting of adverse outcomes to better inform participants and health professionals involved in future trials.

Keywords: adverse outcomes; creatine monohydrate; female; human; safety; supplementation.

Figure 1

Organisation of article review process as a PRISMA 2009 flow diagram.

Figure 2

Overall risk of bias for included studies. Data are presented as percentages of risk assessment across 7 predefined domains.

Figure 3

Individual risk of bias for included studies. Data are presented as risk assessment across 7 predefined domains. + (green)=low risk of bias, ? (yellow)=unclear risk of bias, - (red)=high risk of bias

Figure 4

Incidence of adverse events per participant, stratified by dosing regimens. Within Forest Plot, Study or Subgroup = study stratified by dosing regimens; Events = number of adverse events reported; Total = total number of participants in study group; Weight = amount of information contributed by study; M-H = Mantel–Haenszel model; Random= random effects model. Risk of bias; + (green) = low risk of bias, ? (yellow) = unclear risk of bias, - (red) = high risk of bias

Figure 5

Incidence of gastrointestinal (GIT) events per participant, stratified by dosing regimens. Within Forest Plot, Study or Subgroup = study stratified by dosing regimens; Events = number of adverse events reported; Total = total number of participants in study group; Weight = amount of information contributed by study; M-H = Mantel-Haenszel model; Random=random effects model. Risk of bias; + (green) = low risk of bias, ? (yellow) = unclear risk of bias, - (red)=high risk of bias

Figure 6

Changes in renal blood biomarkers (A) and urine biomarkers (B) within placebo (solid bar) and CrM (hatched bar) groups. Data are presented as % change pre-to post-intervention. Units are expressed as presented in the original manuscripts. BUN = blood urea nitrogen, Alb:Crn = albumin:creatinine ratio.

Figure 7

Changes in hepatic blood biomarkers within placebo (solid bar) and CrM (hatched bar) groups. Data are presented as % change pre- to post-intervention. Units are expressed as presented in the original manuscripts. ALP= alkaline phosphatase; AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = gamma glutamyl transferase.

Figure 8

(A) Difference in body weights per group, pre-intervention, stratified by dosing regimens. Within Forest Plot, Study or Subgroup = study stratified by dosing regimens; Mean = mean body weight per group in kgs; SD = standard deviation; Total = total number of participants in study group; Weight = amount of information contributed by study; I-V = Inverse Variance random effects model. (B) Difference in body weights per group, post-intervention, stratified by dosing regimens. Within Forest Plot, Study or Subgroup = study stratified by dosing regimens; Mean = mean body weight per group in kgs; SD = standard deviation; Total = total number of participants in study group; Weight = amount of information contributed by study; IV = Inverse variance model; Random=random effects model; Risk of bias; + (green) = low risk of bias, ? (yellow) = unclear risk of bias, - (red) = high risk of bias