Higher maternal adiposity reduces offspring birth weight if associated with a metabolically favourable profile

Abstract

Aims/HypothesisHigher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal "metabolically favourable adiposity" on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI). MethodsTo test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two sample MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers. ResultsHigher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (-94 (95% CI: -150 to -38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m2) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller sample sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it. Conclusions/InterpretationOur results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIStudies in non-pregnant people with obesity suggest many people can have a "metabolically healthy" form of obesity, but effects in pregnancy and on offspring are not known. C_LIO_LIMultiple lines of evidence show that higher maternal BMI is causally associated with higher offspring birth weight, and that this may be mediated by the fetal insulin response to higher maternal gestational glucose. C_LIO_LIRecently, genetic variants have been identified, where one allele is associated with higher adiposity but lower risk of type II diabetes and favourable metabolic profile, including lower insulin and glucose levels, so called "metabolically favourable adiposity"; the mechanism is thought to be due to greater subcutaneous adipose storage capacity that leads to higher insulin sensitivity. C_LI What is the key question?O_LIWhat is the effect of maternal metabolically favourable adiposity on birth weight, and how does it compare with the effect of maternal BMI on birth weight? C_LI What are the new findings?O_LIHigher maternal adiposity can lead to lower, not higher birth weight, if it is also associated with a metabolically favourable profile; this contrasts with the effect of higher maternal general adiposity (BMI), on higher birth weight. C_LIO_LIHigher maternal metabolically favourable adiposity causes lower maternal fasting plasma glucose levels, most likely due to higher insulin sensitivity; in contrast higher maternal general adiposity leads to higher maternal fasting plasma glucose levels, most likely due to lower insulin sensitivity. C_LI How might this impact on clinical practice in the foreseeable future?O_LIIdentifying ways of stratifying overweight and obese pregnant women into those with and without metabolically favourable adiposity could allow for targeted management to obtain healthy fetal growth and birth weight. C_LI