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

Fertil Steril. 2022 Jul;118(1):180-190. doi: 10.1016/j.fertnstert.2022.04.001. Epub 2022 May 10.


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; ORadjusted 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]: ORcrude, 0.94; 95% CI, 0.88-0.99; ORadjusted 0.89; 95% CI, 0.84-0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75-0.91; ORadjusted, 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.

Keywords: Mendelian randomization; Smoking; infertility.

MeSH terms

  • Child
  • Cohort Studies
  • Fathers
  • Female
  • Humans
  • Infertility* / diagnosis
  • Infertility* / genetics
  • Infertility* / therapy
  • Male
  • Mendelian Randomization Analysis
  • Mothers
  • Pregnancy
  • Prospective Studies
  • Smoking* / adverse effects
  • Smoking* / epidemiology
  • Smoking* / genetics