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

High smoking intensity, earlier initiation, and not quitting smoking were linked to infertility in women. Mendelian randomization analyses did not validate these associations. Smoking was unrelated to infertility in men.

VOLUME 118, ISSUE 1, P180-190

Authors:

Álvaro Hernáez, Pharm.D., Ph.D., Robyn E. Wootton, Ph.D., Christian M. Page, Ph.D., Karoline H. Skåra, M.Sc., Abigail Fraser, Ph.D., Tormod Rogne, M.D., Ph.D., Per Magnus, M.D., Ph.D., Pål R. Njølstad, M.D., Ph.D., Ole A. Andreassen, M.D., Ph.D., Stephen Burgess, Ph.D., Deborah A. Lawlor, Ph.D., Maria Christine Magnus, Ph.D.

Abstract:

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.