Assessment of male creatinine levels and fecundity in couples planning pregnancy: a national cohort study in China

STUDY QUESTION: Is there an association between male creatinine levels and time to pregnancy (TTP) in couples planning pregnancy? SUMMARY ANSWER: Low and high male creatinine concentrations were associated with reduced couple fecundity. WHAT IS KNOWN ALREADY: Abundant evidence suggests male creatinine dysfunction is associated with infertility in males with kidney diseases. However, the association of preconception creatinine levels with reduced fecundity among general reproductive-aged couples lacks evidence from an in-depth population study. STUDY DESIGN, SIZE, DURATION: Based on the population-based cohort study from the National Free Preconception Check-up Projects, 4 023 204 couples were recruited and met the inclusion criteria from 1 January 2015 to 31 December 2017. They were planning pregnancy and were followed up every 3 months until achieving pregnancy as detected by gynaecological ultrasonography or were followed up for 1 year for the analysis of TTP. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cox regression models were used to estimate hazard ratios (HRs) and 95% CI for creatinine deciles. Restricted cubic spline regression was adopted for the dose-response relationship of creatinine with HRs. R statistical software was used for data analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of the included participants, 2 756 538 (68.52%) couples successfully conceived. The median male serum creatinine was 81.50 μmol/l. Compared with the reference group (78.00-81.49 μmol/l) including the median creatinine, fecundity in the first (≤64.89 μmol/l), second (64.90-69.99 μmol/l), third (70.00-73.99 μmol/l), and tenth (≥101.00 μmol/l) deciles decreased by 8%, 5%, 2%, and 1%, respectively (Decile 1 Adjusted HR 0.92, 95% CI 0.91-0.92; Decile 2 Adjusted HR 0.95, 95% CI 0.95-0.96; Decile 3 Adjusted HR 0.98, 95% CI 0.97-0.99; Decile 10 Adjusted HR 0.99, 95% CI 0.98-0.99). An inverse-U-shaped association was consistently presented among males such that non-inferiority for fecundity was shown when creatinine was in the 81.66-104.90 μmol/l range (P for non-linearity < 0.001). For males over 40 years old, the risk of fecundity impairment was more obvious and the recommended range of creatinine levels for TTP was reduced and more narrow, compared with that for younger males. LIMITATIONS, REASONS FOR CAUTION: Not including the time couples spend preparing for pregnancy before enrolment would lead to an overestimation of fecundity; additionally some couples place pregnancy plans on hold due to special emergencies, which would not have been recognized. Due to the lack of information regarding semen quality, psychological factors, sexual intercourse frequencies, and hazardous environmental factors, we could not adjust for these factors. Some variates were self-reported and dichotomized, which were prone to bias. Direct variables reflecting muscle mass and impaired kidney function were lacking. Thus, extrapolation should be done with caution. WIDER IMPLICATIONS OF THE FINDINGS: Male creatinine is associated with couples' fecundity and the relationship varied by age. This study provides a better understanding of the potential implications and significance of different creatinine levels and their association with the clinical significance regarding couples' fecundity. STUDY FUNDING/COMPETING INTEREST(S): This research has received funding from the National Natural Science Foundation of China (Grant No. 81872634), the Basic Research Funds of Central Public Welfare Research Institutes of China (Grant No. 2023GJZ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), People's Republic of China. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.