Major challenges and threats to the validity and interpretation of systematic reviews and meta-analyses include lack of systematic and transparent conduct and reporting, poor methodological quality of the included studies, risk of random errors, unrecognized and unaccounted statistical and clinical heterogeneity, data dredging in non-predefined statistical analyses, and lack of assessment of the overall quality of evidence.
Lack of systematic and transparent conduct and reporting of systematic reviews is still common, despite efforts at prompting registration and careful reporting. Many systematic reviews are often flawed, redundant and/or misleading .
The methodological rigour of many published trials is not adequate, and most suffer from high risk of systematic errors (bias), which in turn increases the risk of overestimating benefit and underestimating harm . Many statistical analyses are inadequately conducted and reported, and even changed after the completion of a trial . Meta-analyses may not necessarily remove these biases.
Meta-analyses are at further risk of random errors due to repetitive testing and spurious findings . Trial sequential analysis approaches  and other methods may help confer the right amount of uncertainty about the conclusiveness of the results.
Summarising data from various sources increases the risk of heterogeneity. Although heterogeneity may be estimated statistically, currently available approaches, such the Q test and I2 estimates, remain imperfect, weak in detecting heterogeneity and likely give a false sense of reassurance when failing to demonstrate significant heterogeneity .
Overall, the quality of evidence of many systematic reviews and meta-analyses is low because of risks of bias, indirectness, imprecision, inconsistency and publication bias . This has significant impact on the validity of the findings.