Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

OBJECTIVE: To investigate the association between smoking and infertility. DESIGN: Prospective study. SETTING: Nationwide cohort. PATIENTS: 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. INTERVENTION: Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. MAIN OUTCOME MEASURE: Infertility (time-to-pregnancy ≥ 12 months). RESULTS: Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR](crude), 1.19; 95% confidence interval [CI] 1.11-1.28; OR(adjusted) 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: OR(crude), 0.94; 95% CI, 0.88–0.99; OR(adjusted) 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: OR(crud)e, 0.83; 95% CI, 0.75–0.91; OR(adjusted), 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. CONCLUSIONS: We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding. (Fertil Steril® 2022;118:180-90. ©2022 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.