Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study
Authors: Hernáez Álvaro , Rogne Tormod , Skåra Karoline H. , Håberg Siri E. , Page Christian M. , Fraser Abigail , Burgess Stephen , Lawlor Deborah A. , Magnus Maria Christine 
Published: June 2021

ABSTRACTBackgroundHigher body mass index (BMI) is associated with subfertility in women and men. This relationship is further substantiated by a few small randomized-controlled trials of weight reduction and success of assisted reproduction. The aim of the current study was to expand the current evidence-base by investigating the association between BMI and subfertility in men and women using multivariable regression and Mendelian randomization.Methods and findingsWe studied 34,157 women (average age 30, average BMI 23.1 kg/m2) and 31,496 men (average age 33, average BMI 25.4 kg/m2) who were genotyped and are participating in the Norwegian Mother, Father and Child Cohort Study. Self-reported information was available on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear Mendelian randomization validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 15% greater odds of subfertility (95% confidence interval 4% to 28%) in obese women (≥30.0 kg/m2) and 14% lower odds of subfertility (−25% to -3%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 23% greater odds of subfertility (6% to 43%) among obese men and 36% decreased odds (−62% to 7%) among men BMI <20.0 kg/m2. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. The main limitations of our study were that we did not know whether the subfertility was driven by the woman, man, or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2.ConclusionsWe observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization analysis, further supporting a potential causal role of BMI on subfertility.AUTHOR SUMMARYWHY WAS THIS STUDY DONE?Higher body mass index (BMI) in both women and men is associated with subfertility in in observational studies. A few small randomized-controlled trials of weight reduction have reported an increased success of assisted reproduction in women. In addition, women with BMI <18.5 kg/m2 have lower conception rates with assisted reproduction technologies. A non-linear relationship between BMI and subfertility is suggested.We aimed to investigate the association between BMI and subfertility using both a standard multivariable regression and a Mendelian randomization approach.WHAT DID THE RESEARCHERS DO AND FIND?We examined the relationship between BMI and subfertility (time-to-pregnancy ≥12 months) among all men and women in the Norwegian Mother, Father and Child Cohort Study with available genotype information and anthropometric data (34,157 women, 31,496 men).We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization analysis.WHAT DO THESE FINDINGS MEAN?Together with previous observational and trial evidence, findings support a causal effect of overweight/obesity on subfertility in women and men.Our findings expand the current evidence by also indicating that individuals at the lower end of the BMI distribution (<20 kg/m2) may have an increased risk of subfertility.Current advice and support for overweight and obese subfertile couples to lose weight should continue. Additionally, clinicians should consider appropriate advice to those with low BMI on whether they should increase weight to obtain a normal BMI.