Cohort study finds a ‘causal effect’ of high (and low) BMI on subfertility

Published 05 November 2021

A large population study using two analytical approaches finds a consistent association between BMI measurements and subfertility; a predicted BMI of 23 in women and 25 kg/m2 in men was linked to the lowest subfertility risk.

A large population study has found a ‘causal effect’ of obesity on subfertility in both men and women.(1) This cohort analysis from the Norwegian Mother, Father and Child Cohort Study, included a population of 28,341 women and 26,252 men recruited between 1999 and 2008 and found direct associations between high and low BMI and risk of subfertility. A 1 kg/m2 greater ‘genetically predicted’ BMI was linked to 18% greater odds of subfertility in obese women (defined by a BMI of 30 or above), while a 1 kg/m2 higher genetically predicted BMI was linked to 26% greater odds of subfertility among obese men. The results, report the authors, confirm the findings of other observational studies but additionally indicate that even low BMI measurements were associated with subfertility.

The ’genetically predicted’ BMI was based on findings from recent genome-wide association studies which had yielded more than 900 single nucleotide polymorphisms (SNPs) associated with BMI. This allowed the investigators to compute a ‘genetic risk score’ which was applied to those study subjects with full genotype data (based on blood samples from both parents during pregnancy) and pre-pregnancy information on BMI. The subjects also provided self-reported information on time to pregnancy. Overall, around 10% reported some subfertility as defined by time to pregnancy of at least 12 months. The associations were deduced by multivariable logistic regression models and a ‘Mendelian randomisation’ analysis to obtain a genetically predicted BMI.

It was the consistency of results from both these analytical approaches ‘which increases confidence in these findings being causal’. ‘To our knowledge,’ the authors write, ‘studies exploring non-linear associations between BMI and subfertility using multivariable regressions and an MR [Mendelian randomisation] approach have been lacking.’ Causation, however, requires biological plausibility and the authors describe ‘several’ mechanisms explaining the link between high BMI and subfertility. These seem mainly of metabolic origin (insulin resistance, triglycerides, fatty acids), which in turn are linked to impaired endocrine responses in both women and men.

While the headline results of this study reflect those of other observational studies, the authors particularly note the effect of low BMI (<20 kg/m2) on subfertility. This they explain by an effect of ‘undernutrition’ on reproductive function, endocrine processes and pregnancy complications. Thus, with their evidence for a ‘causal’ association of subfertility with both high and low measures of BMI (ie, a non-linear relationship), the authors suggest that BMI values between 20 and 25 kg/m2 are ‘optimal’ for a minimal risk of subfertility.

In their background details to the study, the authors note that an improvement in ART success has not been observed in all RCTs of weight loss after lifestyle modifications and even bariatric surgery – although a recent systematic review of the latter (in spontaneous and ART pregnancies) found that bariatric surgery ‘can greatly influence periconception maternal health with consequences for reproduction, pregnancy and health in later life’.(2)

A recent study of IVF outcomes from 3316 ICSI cycles has also found no difference in blastocyst formation rate and blastocyst morphology between obese and normal weight women as assessed by time-lapse microscopy.(3) The authors here suggested that any explanation for the poorer IVF outcomes found in obese patients ‘are probably due to deficient endometrial receptivity’.

The study reports coincide with publication of a revised ASRM committee opinion on obesity and reproduction which cautions that, ‘although obesity increases the risk of infertility, most men and women with obesity are fertile’.(4) Obesity in women, the report reaffirms, is associated with ovulatory dysfunction, reduced ovarian responsiveness to agents that induce ovulation, altered oocyte as well as endometrial function, and lower birth rates after IVF. In men, reproductive function ‘may be impaired’. The opinion concludes, however, that obesity ‘should not be the sole criteria for denying a patient or couple access to infertility treatment’, but that ‘prepregnancy counseling for couples with obesity should address the reproductive and maternal–fetal consequences of obesity’.

1. Hernáez Á, Rogne T, Skara KH, et al. Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study. Hum Reprod 2021; doi:10.1093/humrep/deab224
2. Snoek K, Steegers-Theunissen R, Hazebroek E, et al. The effects of bariatric surgery on periconception maternal health: a systematic review and meta-analysis. Hum Reprod Update 2021; doi:10.1093/humupd/dmab022
See https://www.focusonreproduction.eu/article/News-in-Reproduction-Bariatric-surgery
3. Bellver J, Brandao P, Alegre L, Meseguer M. Blastocyst formation is similar in obese and normal weight women: a morphokinetic study. Hum Reprod 2021; doi:10.1093/humrep/deab212
4. Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril 2021; doi.org/10.1016/j.fertnstert.2021.08.018

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