Health behaviours prior to pregnancy and fertility outcomes: Triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa)

Introduction: Current advice to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range, and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. Methods: This study uses data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. First, we analysed associations between health behaviours prior to pregnancy (alcohol and caffeine consumption, body-mass index (BMI) and smoking) and multiple indicators of fertility (including number of children, time to conception, and miscarriage) (n=83,128 women, 67,555 men), adjusting for birthyear, education and attention deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility outcomes (n=27,216 women, 26,131 men). Finally, we performed summary-level MR for available outcomes (n=91,462-1,232,091) and conducted multi-variable MR to control for education and ADHD liability. Results: In observational analysis, higher BMI and smoking (and to a lesser extent caffeine) were predominantly associated with reduced fertility outcomes. Unexpectedly, higher alcohol consumption was associated with predominantly improved fertility outcomes. There was little evidence from individual-level MR analyses, except smoking and higher BMI were associated with younger age at first birth in women (mean difference in years, per SD increase in genetic score; smoking: -2.65 (95%CI: -3.57, -1.73); BMI: -0.11 (95%CI: -0.16, -0.08)) and men (smoking: -2.82 (95%CI: -4.07, -1.58); BMI: -0.17 (95%CI: -0.23, -0.11)). These results were replicated in the summary-level MR analysis, however effects attenuated after adjusting for education and ADHD liability. Conclusions: Most observational evidence for associations between health behaviours and fertility was not supported by MR analyses, suggesting possible residual confounding. Evidence from MR analyses supported an effect of smoking and higher BMI on younger age of first birth, but multivariable MR suggested this might be explained by underlying liability to ADHD and low educational attainment.