Assessment of risk of bias and quality of evidence
The methodological quality of the included studies was assessed by two independent reviewers (A.P and S.S..) using the Newcastle Ottawa scale. The scale incorporates domains that include assessment of selection of study groups, comparability of groups and methods ascertainment of the outcome of interest. A point is awarded in a 9-point based system. For the purposes of the present systematic review the two points that are awarded for comparability of groups refer to differences in baseline gestational age at assessment of serum LDH and in maternal age.
Quality of evidence was evaluated under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, ranging from very low to high. More specifically, credibility of evidence was assessed by taking into account the following domains: study limitations, directness, consistency, precision and publication bias. In particular, study limitations were evaluated based on risk of bias assessments (NOS score), while directness was judged using the PICOS (population, intervention, comparison, outcome, study type) approach. To assess consistency and precision, clinically important effects were defined as serum LDH differences of ≥100 U/L, indicating a range of equivalence from -50 to 50 U/L. In this context, consistency referred to the agreement of 95% confidence and prediction intervals for each outcome in relation to clinically relevant effects, while precision assessment was made by taking into account whether 95% CI extended into the range of equivalence.